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A HEPOUT 



ON THE 



PHYSIOLOGICAL ACTION OF CHLOROFORM 



WITH A 



CRITICISM OF THE SECOND HYDERABAD 
CHLOROFORM COMMISSION. 



BY 

W. H. GASKELL, M.D., F.R.S., 

LECTURER ON PHYSIOLOGY IN THE UNIVERSITY OF CAMBRIDGE, 

AND 

L. E. SHORE, M.D., 

DEMONSTRATOR IN PHYSIOLOGY IN THE UNIVERSITY OF CAMBRIDGE. 






PRINTED AT THE OFFICE OF 

THE BRITISH MEDICAL ASSOCIATION, 429, STRAND, W.C. 

1893. 




THE PHYSIOLOGICAL ACTION OF CHLOROFORM, 

WITH A CRITICISM OF THE SECOND HYDERABAD CHLOROFORM COMMISSION. 



Intboductoey Obsebvattons. 

In the summer of 1890, when Surgeon-Lieutenant-Colonel 
Lawrie was In England, he asked one of us (Gaskell) to look 
over the curves of the Second Hyderabad Chloroform Commis- 
sion, and make a report on them, supplementing that report 
with experimental investigation, if necessary. 

At the very outset it was evident that the Commission 
did not sugpry any answer to the most important question 
connected with the action of chloroform — namely, What 
is the reason of the fall of blood pressure which always 
occurs when a large dose of chloroform is administered P 
Before, therefore, it was possible to report on the curves of 
the Commission, it was necessary to make up our minds upon 
the meaning of this fall of blood pressure. For that purpose, 
we have carried out a number of experiments, and propose in 
this paper to give the results of those experiments, as well as 
a criticism of some of the conclusions of the Hyderabad 
Commission. The funds for this research were most gener- 
ously provided by H.H. the Nizam, upon the application of 
Surgeon-Lieutenant-Colonel Lawrie ; and we beg here to 
thank them for their aid in carrying out this investigation. 

As far as the physiological action of chloroform is concerned, 
the controversy which has raged so long about the safety of 
its administration resolves itself into the question of its rela- 
tive action upon the central nervous system and the peri- 
pheral organs. On the one side, we find the evidence given 
by Lawrie and the Hyderabad Commission, that chloroform 
acts essentially, if not entirely, as a paralyser of the central 
nervous system, but does not act directly upon any of the 
peripheral organs ; while, on the other hand, the evidence of 
Snow, and in recent years of the Glasgow Commission, of 
Wood, and of McWilliam, is to the effect that chloroform acts 
directly as a paralyser of the heart, as well as on the nervous 
system. 

So much has been written and spoken about chloroform of 
late years, that it is hardly necessary to write out the history 
of its experimental investigation ; but it is perhaps advisable to 
mention some of the original observations and conclusions of 
Snow in 1858, seeing that at the present time the older ob- 
servations are apt to be overlooked. 

Snow's experiments on animals were performed without the 
graphic methods of modern days, and were largely directed 
towards the investigation of the relative effects upon the heart 
and respiration of air containing chloroform to a varying 
amount. His experiments show that if the air breathed con- 
tains 3 to 6 per cent, of chloroform vapour then respirations 
cease while the heart sounds are very distinct ; but if the air 
contains 8 to 10 per cent, of chloroform vapour then the action 
of the heart is always extremely feeble, even if it does not ac- 
tually cease before the arrest of the respiration ; and on page 
89 he observes with respect to the danger of concentration of 
the chloroform vapour, " If the air the patient breathes never 
contains more than 5 per cent, of chloroform vapour the pulse 
can never be seriously affected by the direct action of chloro- 
form, and the state of the breathing affords the best warning 
against continuing the inhalation too long a time." 

He further says that the pulse sometimes becomes inter- 
mittent or irregular during the administration of chloroform, 
but adds that he has never seen any danger in this condition. 
Also, page 90, "the patient sometimes holds the breath after 
he is unconscious and before he is insensible ; in other cases, 
in the third stage of narcosis, where there is rigidity of 
muscles. In neither case is there danger in this condition per 
se." He points out that after the cessation of inhalation the 
symptoms of poisoning may increase owing to the absorption 
of chloroform still in the lungs. Also struggling and rigidity 
with holding of breath, which usually occurs when the patient 
has nearly absorbed the necessary amount, requires careful 
A 



looking after, owing to the excessive inspirations which follow 
and may lead to the intake of a large amount of chloroform 
unless precautions are taken. 

After the advent of graphic methods of registration we have 
the evidence of the Glasgow Commission in which special 
prominence was given to sudden stoppage of the heart and to 
capricious effects of chloroform. Such effects are seen mainly 
at the beginning of chloroform administration, and are clearly 
free from danger, as asserted by Snow, being simply Nature's 
safeguard against an irritant vapour, as pointed out by the 
Hyderabad Commission. Such effects are: (1) stoppage of 
respiration reflexly through the trigeminus and other nerves ; 
(2) slowing or stoppage of the heart through the vagus nerve 
— both reflex actions for the purpose of preventing access 
of the vapour to the blood and so to the nervous system. 
In this of itself there is no danger; the only danger is in the 
after-effect, as maintained by the Hyderabad Commission ; 
namely, in the likelihood of too large a dose being taken in 
owing to the excessive inspirations. 

It is agreed on all sides that the effect of a large dose of 
chloroform is to cause insensibility, diminution of reflexes, a 
marked lowering of blood pressure, and finally slowing and 
cessation of respiration. 

The Hyderabad Commission does not attempt to explain 
the reason of the fall of blood pressure, though it is evident, 
from the following remarks of Lawrie, that he at all events is 
inclined to attribute it to the action of the drug upon the 
vasomotor centre. He says: 1 "The Commission has given 
no opinion as to the cause of the fall produced by diluted 
chloroform alone. It is obvious from all their experiments 
that the effects of chloroform are first exerted upon the ner- 
vous tissues, the vasomotor centre is very soon involved, the 
respiratory centre becomes paralysed, then the muscular 
tissues become affected, and last of all the heart." 

So also the Glasgow Commission and Wood regard the 
paralysis of the vasomotor centre as a possible factor in pro- 
ducing the fall of blood pressure, but do not attempt to dis- 
tinguish between its share and that of the heart. 

Even McWilliam, 2 who makes so much of the dilatation of 
the heart by chloroform, says: (Par. 17) "The fall of blood 
pressure is in its earlier stages due mainly to the depressing 
effect of the anaesthetic on the vasomotor centre, preceded 
often by a slight stimulation ; the later stages are associated 
with failure of the heart as well as of the vasomotor centre." 
In fact, the fall of blood pressure is looked upon by most -ob- 
servers as largely due to paralysis of the vasomotor centre, 
and yet, as far as we can find out, this conclusion is not 
based upon any direct experimental evidence. Further, see- 
ing that the initial part of the blood pressure fall is that part 
which is especially attributed to the paralysis of the vaso- 
motor centre, and also that the fall of blood pressure is an 
early symptom in chloroform administration, it follows that 
experimental evidence ought not only to show a paralysis of 
the vasomotor centre by the action of chloroform, but also 
that centre ought to be more susceptible to the paralysing 
action of the drug than the neighbouring respiratory and 
cardio-inhibitory centres, seeing that the fall of blood pres- 
sure begins before the respiration shows any signs of para- 
lysis and vagus effects upon the heart can still be produced 
after the blood pressure has commenced to fall. 

Plan op Oub Expebiments. 
In considering the relative share played by the heart and 
the vasomotor centre in the production of this blood pressure 
fall there are two possibilities : 1. The fall of blood pressure 

1 Hyd. Com. Report, p. 244. 

2 British Medical Journal, October isth, October 25th, and November 

1st, 1890. 







may be due in the first instance to failure of the vasomotor 
centre, the heart not being affected until a very excessive 
dose has been given. 2. The fall of blood pressure may be 
due from the very first to a weakening of the heart's action, 
the vasomotor centre not being affected until a very excessive 
dose has been given. 

The object of our investigation then was to determine (1) 
the primary effect of chloroform, and (2) the ultimate effect 
of a large dose on the vasomotor centre and on the heart re- 
spectively. Our object was to separate, as far as possible, the 
application of the drug to the medulla oblongata and to the 
heart, and for this purpose we made, in the first instance, 
the following experiments : 

1. Direct application of chloroform to the exposed fourth 
ventricle. 

2. Injection of chloroform into the jugular vein. 

3. Injection of chloroform into the internal carotid artery. 

4. Injection of chloroform into the vertebral artery. 

In this set of experiments we found, as will appear below, 
a decided difference of effect according as the chloroform was 
injected heartwards or brainwards. "We felt, however, that a 
legitimate objection might be taken to drawing any conclu- 
sions from these experiments as to the behaviour of chloro- 
form when administered by inhalation, because it did not 
necessarily follow that the injection of chloroform into a 
blood vessel was strictly comparable in its effects with chloro- 
form vapour in the blood. We therefore determined to sup- 
plement these experiments by another set, the object of which 
was to administer chloroform by inhalation, and, at the same 
time, to isolate the brain in such a way that it alone might be 
subject to the action of the chloroform, or, on the other hand, 
so that it alone might be exempt from that action. In order 
to do this we have used in each experiment two animals so 
arranged that the brain of the one (called the fed) was supplied 
by the blood of the other (called the feeder), and was therefore 
isolated from its own heart; chloroform could be adminis- 
tered to either animal after the cross circulation was estab- 
lished, with the result naturally, as far as the fed animal was 
concerned, of conveying chloroformed blood to the brain 
only, or to the heart and all other organs with the exception 
of the brain. The necessary procedure for the successful 
carrying out of these experiments was, as can be imagined, 
long and laborious, but the results amply repaid the trouble, 
as will, we hope, be evident from the detailed description of 
these experiments. 

Both sets of experiments point to the same conclusion, 
namely, the fall of blood pressure caused by administration of 
chloroform is due primarily to a weakening of the heart's 
action, and not to a paralysis of the vasomotor centre. On the 
contrary, the primary effect of blood containing chloroform 
vapour on the vasomotor centre is an excitation, causing 
thereby a marked rise of blood pressure, and it is only after 
an excessive dose has been given that there is any evidence 
of any paralysis of this centre. 

In our investigations we have used rabbits and dogs. Most 
of the experiments were made on rabbits, because we desired 
to register the movements of respiration as well as the condi- 
tion of the blood pressure, and, in our opinion, no better 
method exists for the registration of the movements of respi- 
ration, both as regards rate and nature of muscular contrac- 
tion, than that introduced by Head, 3 a method which is only 
applicable to the rabbit, and consists of the direct registration 
of the contractions of an isolated strip of the diaphragm 
muscle itself. In all cases a dose of chloral hydrate was given 
to the rabbit before the experiment commenced, and, in the 
case of dogs, they were always under the influence of acetate 
of morphine before the chloroform was administered. 

The blood pressure, taken either from the carotid or femoral 
artery, was measured by a mercury manometer, recording in 
the ordinary way on Ludwig's kymograph. 

For artificial respiration we used the very efficient apparatus 
designed by the Cambridge Scientific Instrument Company. 
By this apparatus an active withdrawal of air from the lungs, 
as well as an active supply of air, is secured. The rate, depth, 
and character of the respiration, that is, the relative duration 
of the inspiratory and expiratory phases, could be regulated 
with great nicety and maintained with accuracy. 

3 Joum 0/ Physiol., vol. x, p. 1. 



CojIPABISON OF THE INJECTION OF ChXOHOFOBM INTO THB 

J ugulab Vein and into the Bbain Abtebies : 
Injection into Jtj&tjxab. 

The Hyderabad Commission assert that in Experiment 92 
repeated injections of 20 minims of chloroform were made 
into the jugular vein, and its effect was not to paralyse the 
heart, but to produce anaesthesia and a gradual fall of blood 
pressure exactly as if the chloroform had been inhaled. The 
amount of chloroform injected into the circulation in this 
experiment was 180 minims, given in 20-minim doses at vary- 
ing intervals of time during 46 minutes. In other words, 
this large amount of liquid chloroform was said to have been 
sent into the circulation, and it was clear from its anaesthetic 
action on the brain and its effect on respiration that it circu- 
lated over the whole vascular system, and yet it produced 
exactly the same effects as if the chloroform had been in- 
haled. 

Our experiments agree with those of the Hyderabad Com- 
mission as to the nature of the effect produced when chloro- 
form is injected into the jugular vein; we do not, however, 
interpret these effects in the same way. 

AVhen a small amount of chloroform is injected into the 
jugular of a rabbit it always causes a fall of blood pressure, 
during which (1) the excursions due to the heart beats are 
diminished in size, and (2) the respiratory curves on the 
blood-pressure tracing are very much smaller, and may, in- 
deed, almost vanish. During this fall of blcod pressure the 
respiration is not necessarily altered either in rate or force; 
the blood pressure then recovers either entirely or partially, 
the pulse and respiratory excursions of the blood- pressure 
curve become again more conspicuous, and with the rising 
pressure the respiration may be affected, and the anaesthesia 
become more profound. Repeated small injections depress 
the blood pressure more and more, the pulse excursions 
become less and less visible until, when the pressure is very 
low, they vanish altogether; the respirations, after having 
continued vigorously for a long time, gradually slow off with 
diminishing force of contraction, and finally cease at a time 
when the heart beats have long ceased to be visible on the 
blood-pressure tracing. 

Such a sequence of events is clearly to be explained by the 
gradual weakening of the heart's contractions in consequence 
of the injection, with the final result of a gradual cessation of 
respiration ; and it is noteworthy how the heart is capable of 
recovering itself after each injection, for some considerable 
time at all events. 

In such a case as this it may be said, without fear of contra- 
diction, that death is due to failure of the heart's action, even 
although it may be found, on opening the chest, that the 
ht-art is very feebly beating after the respiration has stopped. 
The type of this effect of the injection of chloroform into the 
jugular vein is given in the following table taken from an 
experiment on December 11th, 1890, and is illustrated by the 
tracings in Fig. 1. 

It is impossible to reproduce the whole length of the trac- 
ing from which this table was compiled, so we have endea- 
voured, in this case and in others, to give the general effect 
of the experiment by the publication of portions of the origi- 
nal tracing taken at the times indicated in the corresponding 
table. 

In all the figures, with the exception of Figs. 6, 7, 8, 9, 10, 
the upper tracing records the contractions of the slip of dia- 
phragm, the upstroke corresponding to the contraction of 
the muscle, and therefore to a movement of inspiration. The 
lower tracing is that of the blood pressure, and is recorded from 
the carotid artery, except in Figs. 6, 7, 8, 9, 10. The points 
in these two tracings which correspond as regard time may 
be seen by the two short vertical lines drawn on each figure. 
The base line, or line of zero pressure, was carefully deter- 
mined at the end of each experiment, and its position is 
shown in each figure. In all cases a record of time in seconds 
was taken, an example of which is reproduced in Fig. 2 upon 
the base line. An electric signal marker was also attached 
to the kymograph by means of which the moment of applica- 
tion of chloroform or other important event was registered. 
The tracings all read from right to left. 

Injection of chloroform into the jugular vein frequently 
ca lses a fatal result in quite a different manner, death occur- 
ring through failure of the respiration, and not through 



o 



Fig. 1.— December 11th, 1800. Rabbit. Injection of Chloroform 
into Jvgular Vein. 



Time. 


Blood 
Pressure 


Respira- 
tion Rate 


Amount 
of Chlo- 
roform 
Injected. 


Remarks. 




iu mm. 


per min. 




H. M. s. 










1 33 


70 


23 


— 


a in Fig. 1 represents a portion of 
tracing at this time. 


1 34 8 


70 


23 


l m 





1 34 38 


45 


— 


— 


b in Fig. 1 shows disappearance of 
respiratory curves. 


1 36 


62 


32 


— 


c in Fig. 1 shows recovery of blood 
pressure. 


1 36 27 


62 


32 


l m 





1 37 


40 






Respiratory curves nearly disap- 
peared, and did not return 
throughout experiment. 


1 38 


56 


— 


— 


d in Fig. 1. 


1 38 22 


56 


— 


i m 





1 38 46 


40 


32 


— 


Pressure did not recover before 
next injection. 


1 40 21 


39 


32 


l m 





1 41 


38 


32 


— 


e in Fig. 1. 


1 42 


38 


— 


— 





1 43 


38 


— 








1 44 


38 


— 


— 





1 15 


38 


— 


— 





1 45 32 


38 


— 


1 OT 





1 47 


36 


— 







1 48 12 


36 


— 


2 m 





1 49 30 


34' 


— 


— 





1 51 23 


34 


— 


2 m 





1 52 30 


32 


34 


— 


/ in Fig. 1 ; pulsations barely 
visible. 


1 53 30 


30 








1 55 


29 


33 


— 


g in Fi£. 1. 


1 67 


28 


— 


— 


Pulsations still visible. 


1 58 


24 


— 


— 


Pulsations not visible. 


1 59 


23 


22 


— 





1 59 22 


23 


— 


2 m 





1 59 62 


23 


— 


— 


Last respiration, h in Fig. 1. 


2 15 








Artificial respiration was put on 
and continued until 2.52, when 
it was stopped, as animal was 
quite dead. Heart examined at 
3.3 and was found to be cold, 
still, and dilated. 



Fig. 2.- 


-December 10th, 1S90. Rabbit. Injection of Chloroform 
into Juaular Vein. 


Time. 


to 

u 
3 
m 

? a 

£3 

•d a 
o---< 
o 

3 


■£ a 

P. A 


SSI 

oo.£ 


Remarks. 


H. M. 3. 
4 20 30 

4 21 60 
4 22 2 

4 22 30 
4 23 30 
4 25 

4 25 30 

4 25 45 
4 27 
4 28 30 
4 28 45 

4 30 
4 31 
4 32 

4 33 
4 34 


86 

88 
50 

60 

78 
8S 

88 

42 
86 
80 
29 

52 
51 
50 

12 
4 


42 

42 
51 

44 
43 
42 

42 

48 
41 
41 

35 
27 
12 


1 nt 

1 m 
1 m 


Respiratory [curves of blood pressure well 
marked. 

Temporary quickening of respiration. Respi- 
ratory curves diminished during the fall of 
blood pressure. 

The blood pressure had entirely recovered 
from the effects of the previous injection. 

The effect of this injection is shown in Trac- 
ing a. 

Temporary quickening of respiration. 

Active expirations alternating with inspira- 
tions. Marked diminution of size of respi- 
ratory curves of blood pressure and of pulse 
excursion. 

Respiratory curves of blood pressure and 
pulse excursions recovered. 

Respiration markedly slowing. Strip of dia- 
phragm muscle elongating. 

Pulse excursions and respiratory curves of 
blood pressure very prominent, as seen in 
the beginning of Tracing b. 

Immediately afterwards a few gasping respi- 
rations, and then absolute cessation of 
respiration as shown in end of Tracing 6. 
Heart at the time beating well. After ces- 
sation of respiration blood pressure fell 
quickly, aud at 4.39, on examining hea-t, 
auricles and vent'icles were still and inex- 
citable, the right ventricle being much di- 
lated, and the left slightly. 



A 2 



failure of the heart. In these cases the blood pressure re- 
covers after every injection, and finally the respiration ceases 
at a time when the blood pressure is fairly high, and the 
heart is beating well. An example of this effect is given in. 
the preceding table, taken from an experiment on December 
10th, 1890, and is illustrated by the tracings in Fig. 2. 

In other cases the respiration fails with perhaps the very 
first injection, simultaneously with the fall of blood pressure. 
Such an experiment as that of December 10th shows that the 
heart has managed to rid itseli of the chloroform after each 
successive injection, and consequently the blood pressure 
recovers either entirely or partially ; the chloroform thus got 
rid of by the heart has then passed to the medulla oblongata 
in amount sufficient to hinder, and finally to paralyse, the 
action of the respiratory centre. Further it suggests that this 
chloroform in the medulla oblongata does not paralyse the 
vasomotor centre simultaneously with the respiratory ; for at 
the time of cessation of respiration the blood pressure was 
rising rather than falling. 

When the respiration ceases with the very first injection, 
simultaneously with the fall of blood pressure, this means 
that in these cases some of the chloroform has managed to 
pass into the medulla oblongata with the very first beats of 
the heart. 

Injection into Bhain Artebies. 

Upon the assumption that the injection of chloroform into 
the vascular system acts in the same way as inhalation, it 
follows that injection of chloroform into the brain arteries and 
so directly to the vasomotor centre ought most markedly to 
produce a fall of blood pressure due to the paralysis of the 
vasomotor centre, if the inhalation of chloroform causes a fall 
of blood pressure mainly because it paralyses the vasomotor 
centre. On the contrary, if in reality the injection of chloro- 
form into the jugular vein causes a fall of blood pressure by 
the weakening of the heart's beat, then naturally such a fall 
would not occur upon injection into the carotid or vertebral 
arteries until an amount of chloroform sufficient to affect 
the heart had passed through the brain region. 

We have injected chloroform in small amounts into one of 
the carotid arteries (in all cases the external carotid was first 
ligatured) or into one of the vertebrals, and have found that 
in both cases the effect of the injection is to cause a rise of 
blood pressure, and not a fall ; in both cases the respiration 
ceases when the blood pressure is still high ; in both cases the 
conjunctival reflex is abolished, although naturally more 
quickly when the injection is made into the carotis. The 
contrast between the injection into one of the brain arteries 
and into the jugular vein is most marked ; in both cases the 
production of anaesthesia and the cessation of respiration is 
brought about by the action of the drug very much in the 
same way as in ordinary inhalation ; in both cases the injec- 
tion is not necessarily associated with signs of strong irritant 
action upon the nervous system. Occasionally upon the 
first injection into the carotis a certain amount of contraction 
of various muscles takes place; but not only is there no such 
sign upon subsequent injections, but also the injections of 
normal saline solution may produce the same effects. 

Chloroform injected into the vertebral artery does not pro- 
duce quite the same effects as when injected into the carotis ; 
such differences are of considerable interest from a physio- 
logical point of view, although they do not affect the main 
argument as to the action of chloroform. These effects 
may all be summed up by the statement that chloroform first 
excites, then paralyses, the different centres in the medulla 
oblongata. 

Contraction of various muscles and excessive rapid respira- 
tory movements usually take place when chloroform is first 
injected into the carotis ; subsequent injections, however, 
show less and less sign of any primary excitation of muscles, 
and at the same time the conjunctival reflex is abolished, so 
that the primary excitation effects upon the muscular system 
of the body appear to be connected rather with the injection 
of the chloroform into the higher parts of the brain than into 
the medulla oblongata. In confirmation of this supposition 
it is found that muscular movements are much less likely to 
be produced when the chloroform is injected into the ver- 
tebral than when it is injected into the carotis. 

Injections into the carotis or into the vertebral both kill 
the animal invariably by causing ceseaiion of the respiration. 






! 



Ji 






•?i 



<5 
4 



In both cases the respiration becomes markedly slower 
before it ceases, and, as a rule, the final stoppage takes place 
with great suddenness. We see, however, a very marked 
difference between the carotis and vertebral injections as far 
as each individual contraction of the diaphragm is concerned. 
Carotis injections not only slow, but produce also a remark- 
able lengthening of each individual contraction, as is seen in 
Fig. 3, 3, so as to produce a type of respiration called by 

FlG. 3. — December 11th, 1890. Rabbit. Injection of Chloroform 
into Internal Carotis. 





Blood 


Respira- 


Amount 
of Chlo- 




Time. 


Pressure 


tion Rate 


.Remarks. 




in mm. 


per min. 


Injected. 




H. M. S. 










* 57 


76 


48 


— 


Tracing a. 


4 67 17 


— 


— 


— 


Left vagus cut. 


4 67 25 






— 


Right vagus cut, leading^to rise of 
blood pressure. 


4 68 


102 


32 


— 





4 58 30 


100 


34 


— 





4 59 30 


102 


38 


l m 


1 m injected into external carotid, 
and so to internal carotid. Trac- 
ing b. 


too 


144 


35 




Sudden slowing of ventricularbeat 
to half previous rate ; this lasted 
1 min. 20 sec. 


6 30 


144 


36 


— 


Tracing c 


5 1 20 






— 


Contractions of abdominal and 
limb muscles. 


6 6 30 


142 


18 


— 


Tracing d. 


6 7 50 


128 






Inspiratory movements suddenly 
ceased 8 min. 20 sec. after injec- 
tion. Tracing e. 


5 9 


24 





— 





6 10 


12 





— 


After this heart beats no longer 
visible on tracing. 


6 40 








Chest opened, heart still, not 
dilated. 



Fig. 4- 


-July 7th, 1891. 


Rabbit. 


Injection of Chloroform in Dis- 


tal End of 


Subclavian, and so to Vertebral Artery. 




Blood 


Respira- 


Amount 
of Chlo- 




Time. 


Pressure 


tion Rate 


R era ark 3. 




in mm. 


per min. 


Injected. 




H. M. s. 










11 47 


78 


49 


— 


Tracing a. Vagus nerves not cut. 


11 47 7 






1 m 


Contractions of abdominal and 
limb muscles, in consequence of 
which the respiration lever be- 


















came shifted in position and re- 










quired readj ustment, so that 










levels of respiratory tracing 










before and after injection do 










not correspond. 


11 48 30 


90 


42 


— 


Tracing o. 


11 49 30 


72 


42 


— 





11 50 36 


67 


42 


l m 


The last respiration occurred at 
ll h. 50 m. 41 s., as shown in 
Tracing c. 


11 61 30 


102 


— 


— 


Pressure falling ; Tracing d. 


11 53 30 


50 











11 54 30 


47 


— 


— 


Tracing c 


11 55 30 


38 


— 


— 





11 56 30 


25 






Heart beats very regular and con- 
spicuous ; Tracing /. 



Marckwald 4 inspiratory spasms ; this type of respiration is 
frequently associated with a steady shortening of the muscle 
Btrip, as though the tonic contraction of the diaphragm was 
increased by the injection of chloroform into the carotis. On 
the other hand, chloroform, when injected into the vertebral, 
causes a slowing, with a diminishing strength of contraction, 
and a relaxation of the diaphragm strip ; there is here no sign 
of any lengthening of each contraction, but, on the contrary, 
the contractions diminish steadily in extent (see Figs. 4 
and 5, a, b, c). At a later stage of the injection into the ver- 
tebral, it frequently happens that the relaxed condition of the 
diaphragm muscle gives way to a condition of tonic contrac- 
tion, just as though the chloroform had, upon the first injec- 
tion, reached and affected some part of the nervous centre 
* Movements of Respiration, trans, by McKendrick. 



concerned with inhibition of the respiratory contractions, 
and, later on, had reached some higher part, so as to affect 
respiration in the same way as injection into the carotis. 

A very similar difference in action is seen on the blood 
pressure tracings when chloroform is injected into the verte- 
bral and carotid arteries respectively ; in both cases the main 
result is a marked rise of blood pressure, but, in the case of 
vertebral injections, that rise is often preceded by a pre- 
liminary fall of slight extent, a good deal resembling the fall 
of pressure which can be obtained by stimulation of the 
depressor nerve (see Fig. 5, a, b, c). 

Another difference in the blood-pressure curve consists in 
the frequency of occurrence of well-marked periodic undula- 
tions, resembling Traube-Hering curves, after injection into 
the vertebral, in comparison with their rarity after carotis 
injections. The effects produced by injection into the carotis 
and vertebral arteries respectively are illustrated by the 
tables and tracings of December 11th, 1890 (Fig. 3), July 7th, 
1891 (Fig. 4), and July 9th, 1891 (Fig. 5). 

Fig. 5. — July 9th, 1891. Rabbit. Injection of Chloroform 
into the Vertebral Artery by means of a Cannula placed in the 
Subclavian distal to the Vertebral ; Vagi Intact. 





a 


a 


■m9 








o U 


o S« 




Time. 




3 ° 

p.* £ 


3£» 

2 o* 


Ee marks. 




u 


t'A 


5-a 






Ph 


M 


<u 




H. M. S. 










1 38 


70 


82 


— 


Tracing a. 


1 38 30 


70 


82 


0.25 m 


No movement whatever. 


1 39 30 


57 


62 


— 


Tracing &. 

Marked diminution in strength of contrac- 


1 40 


54 


62 


— 










tions of the diaphragm slip, coincident with 
the slowing. 
Tracing c. From this point the blood pres- 


1 40 30 


52 


62 













sure began to rise, and was accompanied by 










a steady increase of the size of the dia- 










phragm contractions. 


1 41 


53.5 


62 


— 





1 41 30 


59 


52 


— 


Tracing d. 


1 42 


70 


52 


— 


TraciDg e. The contractions of diaphragm 
had now reached the maximum. 


1 42 30 


74 


36 


— 





1 43 30 


68 


25 


. — 





1 43 43 


64 






Tracing/, showing'the last respiration. The 
mean blood pressure continued at 64 for 
half a minute after the last respiration, and 
then began to tali. 



In one case of injection into the carotis, the first injection 
caused a marked primary fall of blood pressure, the respira- 
tory contractions were not lengthened, and the Traube-Hering 
curves were well marked ; in fact, in this instance the chloro- 
form seems to have reached mainly that part of the central 
nervous system which is supplied by the vertebral artery. 

In whichever artery the chloroform is injected, the rise of 
blood pressure is ultimately followed by a fall ; this fall takes 
place in both cases after the respiration has ceased, the differ- 
ence between them being that, when the injection is made 
into the carotis, the fall of blood pressure usually occurs 
suddenly, and is absolutely coincident with the cessation of 
respiration, as in Fig. 3, while, in the case of injections into 
the vertebral, the pressure may continue high for some little 
time after the cessation of respiration, and then gradually 
sink, as in Figs. 4 and 5. 

This fall of pressure in carotis injections coincident with a 
sudden cessation of respiration appears to be due to the 
chloroform paralysing the vasomotor centre at the same time 
as the respiratory centre ceases to act, for, in the first place, 
there is never an asphyxial rise of blood pressure after the 
respiration has stopped such as is always observed if the 
vasomotor centre is intact, and, in the second place, stimu- 
lation of a sensory nerve is unable to cause the pressure to 
rise. On the other hand, the characteristic of injections into 
the vertebral is an asphyxial rise of pressuie after respiration 
has ceased (see Fig. 4 c), and the vasomotor centre is found 
to be susceptible to the action of such a nerve as the 
depressor. Again, cessation of respiration is caused by a 
very much smaller amount of chloroform when injected into 
the vertebral artery than when injected into the carotis; 



thus, a single injection of as small an amount as |iu has 
sometimes proved sufficient in the former case (for example, 
Fig. 5), while in the latter from 1 to 2 in. are necessary to 
produce any effect, and usually three or four injections of 1 in 
each must be given before the animal ceases to breathe. It 
is worthy of notice that the primary fall of blood pressure 
which occurs in many eases upon injection into the vertebral 
is seen only when the amount injected is small, such as J n ; 
with larger doses, such as 2 n, the blood pressure rises imme- 
diately after the injection. 

In many cases when the injection is made into the carotis, 
a well-marked slowing of the heart occurs soon after the injec- 
tion, and it is striking to see how these slow beats of the heart 
are unable to lower the blood pressure, owing to the simul- 
taneous stimulation of the vasomotor centre, as is well shown 
in Fig. 3 a. In this case the slowing of the heart observed 
cannot be attributed to stimulation of the vagus nerves, for 
both vagi were cut before the chloroform was injected into the 
carotis. In other instances where well-marked slowing was 
obtained in consequence of chloroform administration, such 
slowing was undoubtedly due to vagus stimulation, for the 
effect was dependent on the integrity of the vagi. We have, 
however, observed in the course of our experiments many in- 
stances similar to the one quoted, where undoubtedly, owing 
to the fact of previous section of the vagi, some other ex- 
planation must be found ; and careful measurement has 
shown us that in the majority of such cases of slowing, the 
rate of beat was diminished to exactly half the immediately 
preceding rate, as in the instance quoted. This suggests very 
strongly that the slowing in question is an indication of a 
partial block between auricle and ventricle, in consequence of 
which the ventricle responds only to every second auricular 
contraction, a phenomenon which is well known to occur in 
the hearts of both cold- and warm-blooded animals. We have 
observed this peculiar form of slowing under many different 
circumstances, but have not yet been able to make up our 
minds as to the paramount condition for its occurrence; in 
some cases it has appeared to be associated with an asphyxial 
condition of the blood ; it certainly is not necessarily de- 
pendent on the presence of chloroform in the blood, for we 
have never observed it after the injection of chloroform into 
the jugular. It is not advisable to discuss the question 
further in this place, but we hope to be able to throw further 
light upon the causation of such a dropping of beats upon a 
subsequent occasion. 

Chloroform: applied to Fourth Ventricle. 

Finally, to finish up with the effects produced by the direct 
action of chloroform on the nervous centres, we have found 
that the respiration can be easily stopped by the direct appli- 
cation of one or more drops of chloroform to the fourth ven- 
tricle of the brain. We have not as yet made a sufficient 
number of such experiments to enable us to discuss the 
differences observed in connection with the differences of 
effect of the carotis and vertebral injections. 

It is remarkable how small an effect is produced on the 
anaesthetised animal by the opening of the atlo-occipital 
membrane; a large amount of cerebro-spinal fluid runs out 
as a rule, yet neither the respiration or the blood pressure is 
appreciably affected ; when the chloroform is first applied 
muscular movements often occur and the respirations are 
increased in depth and frequency. Upon the application of 
a second drop no movements of the animal take place as a 
rule, but the respiration is temporarily quickened and in- 
creased. The cessation of respiration takes place gradually, 
not suddenly ; the diaphragm contractions become weaker 
and weaker, and finally cease. At the commencement of this 
weakening each contraction for some time is apt to be 
lengthened as in the case of carotis injections. The para- 
lysing effect on the respiration of the chloroform, when ap- 
plied to the fourth ventricle, is its most striking effect, and 
is in marked contrast to the action of such a stimulant as 
nitrate of silver, which, according to Gad, 5 does not stop 
respirations when applied to the fourth ventricle. 

The effect on the blood pressure is not well pronounced, as 

far as can be judged from the few experiments we have made ; 

in some cases there is a slight primary fall followed by a 

slight rise ; in others a rise only, without any preliminary 

5 Verhandl. der physiol. Gesellsch. , 27th June, 1890. 

B 2 



fall. The respiratory blood pressure curves are apt to be very 
well pronounced, and the gradual fall which takes place with 
the gradual cessation of respiration is not broken by an 
asphyxial rise. Periodic undulations resembling Traube- 
Hering curves were not observed as the result of the applica- 
cation of chloroform to the fourth ventricle. 

From these experiments we may draw the conclusion that 
chloroform, whether injected into the cerebral arteries, or ap- 
plied directly to the medulla oblongata, first stimulates, then 
paralyses the parts of the brain with which it comes in con- 
tact : thus the stimulation of the respiratory centre is shown 
by increased frequency and force of the contractions of the 
diaphragm strip; these last but a very short time and then the 
respiratory movements become slower and weaker or slower 
and longer up to complete cessation, or cease somewhat sud- 
denly. The stimulation of the cardio-inhibitory centre may 
be shown by the occurrence of heart slowing dependent upon 
the integrity of the vagus nerves ; this effect also is seen 
only for a short time after injection. The stimulation 
of the vasomotor centre is shown by the marked rise 
of blood pressure, which continues for a long time and 
gives way ultimately to a paralysis, as shown by the absence 
of any asphyxial rise of pressure after respiration has ceased, 
and also by the absence of any reflex rise of pressure upon 
stimulation of a sensory nerve. Perhaps also the presence of 
the periodic undulations resembling Traube-Hering curves 
indicates the action of a strong stimulus upon a less excitable 
centre, as seems to be the case in many instances of periodic 
rhythmical activity of the central nervous system. 

Comparison or Chloroform Injection and Chloroform 
Inhalation. 

These experiments point directly to the conclusion that 
chloroform causes a fall of blood pressure by the weakening 
of the heart's contractions and not by a paralysis of the vaso- 
motor centre ; when, however, we attempt to explain the 
effects of chloroform inhalation by the experience thus gained 
we must always remember that liquid chloroform possesses 
a much more powerful irritant action upon the tissues than 
the vapour of chloroform. This is naturally only a question 
of degree, for the stimulating action of strong chloroform 
vapour is shown most markedly by the reflex effects produced 
upon the nasal and pharyngeal membranes. Although, then, 
we should expect for this reason that injection of chloroform 
into the vascular system should produce stronger signs of 
irritant action than its inhalation, yet there can be no doubt 
that these experiments show that such injections of chloro- 
form, whether brainwards or heartwards, do produce also 
anaesthesia and paralysis of respiration resembling in effect 
the symptoms seen upon inhalation of the drug. We are 
therefore, it seems to us, justified in concluding that although 
these experiments are not of themselves absolute proof of 
the action of chloroform when inhaled, yet they support 
rather than oppose the view that chloroform when inhaled 
differs in its action from chloroform when injected in degree 
rather than in kind, and afford therefore valuable evidence of 
the action of chloroform if they prove to be in accordance 
with the evidence given by other experiments in which 
chloroform was brought into the blood by direct inhalation. 
Another possibility must be borne in mind when discussing 
the value of these experiments, namely, the possibility that 
fluid chloroform when injected into an artery may cut off the 
blood supply from one or more vascular areas supplied by 
that artery, either because the fluid itself obstructs some of 
the small arterioles owing to its cohesive power and im- 
miscibility, or because its irritant action causes capillary 
stasis, and so blocks the flow through the area in question. 
In either case the effect produced in any experiment would 
depend upon the position of the small vessels which were 
blocked rather than upon the specific action of the drug. 

Undoubtedly the effects produced by chloroform when in- 
jected into the cerebral arteries resemble in many respects 
those produced by a blocking or ligature of those arteries. 
Thus the characteristic lengthening of each contraction of the 
diaphragm when chloroform is injected into the carotis re- 
calls forcibly to mind the respiratory spasms described by 
Marckwald when the higher brain paths connected with 
respiration as well as the vagi nerves were cut, and Marck- 



ward 8 has shown that the same kind of elongated spasmodic 
respiration can be obtained by the injection of wax into the 
carotis so as to block the arteries supplying the posterior 
corpora quadrigemina, if at the same time the vagi nerves 
are cut. Further, Marckwald has shown that such elongated 
respiratory spasms can be cut short so that the type of respi- 
ration more nearly resembles the normal by the stimulation 
of such inhibitory nerves as the superior laryngeal or trigemi- 
nal. Our experiments have shown us that the lengthened 
diaphragm contractions produced by injection of chloroform 
into the carotis can also be cut short with a consequent 
quickening of the rate of respiration when a stimulating 
vapour, such as ammonia or chloroform, is applied to the nose. 
In Marckwald's wax injection experiments the spasmodic 
type of respiration was caused by the complete removal of 
the regulating influence of the lungs on the respiration in 
combination with a partial removal of the regulation from 
the higher brain regions. In our experiments, when the vagi 
nerves were intact, it was easy to show that their regulating 
influence was not impaired to any very great extent, for every 
inflation or suction was still able to produce the well-known 
Hering-Breuer effects described by Head, 7 so that if 
the prolonged respiratory spasms caused by wax injec- 
tion and ours caused by chloroform injection have any 
common ground of origin, that common cause must be sought 
for in the paralysis of higher brain paths combined with a 
possible diminution of the regulating power of the vagi 
nerves. 

comparison op chloroform injection and llgatore of 
Brain Arteries. 

Again, it is interesting to compare the effect of ligature of 
the four brain arteries with the effect of injection of chloro- 
form into them. We have made a number of experiments 
for the purpose of observing the sequence of events which 
follows ligature of the four brain arteries. In most cases the 
two subclavian arteries were tied proximal to the vertebrals, 
as well as the vertebrals and carotids. In order to estimate 
the extent of the circulation in the brain after ligature of 
these vessels, we placed a cannula in the peripheral end of 
the carotis as well as the ordinary blood- pressure cannula in 
the end connected with the heart, and tied the external 
carotis and auricular arteries as well as the superior thyroid. 
In this way the only communication with the cannula is by 
way of the internal carotis, and the blood pressure measured 
is that in the circle of Willis. This method was used by 
Hiirthle. 8 It gives a rough-and-ready test of the amount of 
diminution of the blood in the circle of Willis, and also of 
the efficacy of the ligatures round the vertebrals and carotids. 
With the ligature of each vessel the circle of Willis pressure 
falls, while the ordinary blood pressure rises, and, finally, 
when all four vessels are ligatured, the pressure in the circle 
of Willis is very low, and then falls very slowly, nearly to 
zero— that is to 3 to 5 mm. Hg, while at the same time the 
ordinary pressure is very high. Further, it is clear that such 
a proceeding as stoppage of the heart by vagus stimulation 
must produce a fall in both blood-pressure curves as long as 
the brain arteries are open, while naturally it would produce 
a fall in only the systemic blood-pressure curve if the closure 
of the four brain arteries has been efficiently performed. 
This control we found to be quite satisfactory ; as long as one 
vessel was undamped or unligatured then both blood pres- 
sures responded to the peripheral end of the vagus nerve. 
When they were all clamped no sign of a fall was to be seen 
in the circle of Willis pressure curve, although naturally the 
fall in the systemic blood-pressure curve was as great as ever. 

Further, the efficiency of the ligatures was seen by opening 
the atlo- occipital membrane after death, when it was found 
that no cerebrospinal fluid ran out, and that the fourth 
ventricle looked white and bloodless. As a rule the last 
artery to be closed was the carotis on the left side, the two 
ends of the carotis on the right side having been previously 
fixed in connection with the two mercury manometers. A 
respiratory tracing was not taken, but the condition of the 
respiration was noted occasionally. It was found, as is well 
known, that the ligature or clamping of the last artery caused 
considerable struggling, the well known Kussmaul-Tenner 

6 Zeits. /. Biol., xxvi, 259. 

7 Loc. cit. 

8 Pflilger'e Archiv, vol. xliv, p. 674. 



convulsions, and violent respirations ; if, however, the clamp 
was immediately taken off these ceased very quickly. By 
putting on and taking off the clamp at frequent intervals, 
taking it off whenever the animal commenced to struggle, we 
were enabled finally to leave the clamp permanently on with- 
out any struggling, and we always found that complete 
closure in this way was followed by a very marked rise of 
blood pressure in the cannula connected with the heart, and 
an equally marked fall of pressure in the cannula connected 
with the circle of Willis ; stimulation of the peripheral end of 
the vagus then produced no effect on this latter pressure. In 
no case have we seen any attempt at a spontaneous recovery 
of blood pressure in the circle of Willis, much less an increase 
of that pressure above its original height, as mentioned by 
Oorin," provided that the subclavians were ligatured proximal 
to the vertebrals ; in fact, our experiments agree closely with 
Hiirthle's, and we conclude, as he does, 10 that there is no 
evidence of the establishment of any efficient collateral circu- 
lation after the ligature of the four brain arteries. It is, how- 
ever difficult to believe that no blood whatever reaches the 
medulla oblongata, seeing that, as will be explained later, 
chloroform still appears able to produce an effect upon 
respiration. The effect of this cutting off of the circulation to 
the brain is in all cases death by failure of respiration, and it 
is remarkable how long a time the animal is able to continue 
to breathe with the blood supply to the medulla oblongata 
cut off. In our experiments respiration has continued 
for a length of time, varying between eight minutes 
to thirty minutes after the closure of the last 
blood vessel. In all cases the rate of respiration becomes 
slower and slower, so that the stoppage is a gradual one. 
Throughout the whole time during which the respiration 
lasts the aortic blood pressure, which had become very high, 
immediately after the ligature of the last artery remains high, 
the amount of fall being very slight, and the height at the 
time of cessation of respiration is greatly above the normal 
blood pressure as seen before the brain arteries were ligatured. 
The blood pressure does not fall to any extent until after the 
respiration has ceased. This long continued high blood 
pressure is further characterised by the presence of regular 
periodic undulations, which are in many cases remarkably 
regular, and resemble these seen when chloroform is injected 
into the vertebral artery. Finally, the ligature of the brain 
arteries produces a complete anaesthesia, as shown by the 
absence of any corneal or conjunctival reflex before the 
respiration ceases, so that in this case, as in the case of injec- 
tion of chloroform into the brain arteries, paralysis of the 
higher centres occurs first, then paralysis of the respiratory 
centre, and finally paralysis of the vasomotor centre. Primary 
excitation of the cardio-inhibitory centre, as evidenced by a 
slowing of heart rate soon after the complete closure of the 
brain vessels, is clearly indicated on some of the curves. We 
see then that an insufficient supply of blood to the medulla 
oblongata causes an excitation, followed by paralysis, of the 
various centres situated there, and that, just as in the 
case of chloroform injection, the excitation of the vasomotor 
centre lasts so much longer than that of the respiratory centre 
as to keep the blood pressure high during the time the 
respiration is failing, and even up to the time of its stoppage. 
In both cases the vasomotor centre is ultimately paralysed, 
for it is impossible in either instance by means of artificial 
respiration to prevent the blood pressure from falling after 
the cessation of natural respiration. 

Comparison of Action of Chloroform and of Othee 
Agents on the Medullary Centres. 

The resemblance in the sequence of events connected with 
the respiratory and vasomotor centres when the brain arteries 
are ligatured, and when chloroform is injected into those 
arteries, emphasises one most important conclusion, namely, 
that it is not necessary or even probable that a paralysing 
agent should paralyse these two neighbouring centres simul- 
taneously, the evidence is rather in the direction that the ex- 
citation of the vasomotor centre will outlast both the excita- 
tion and subsequent paralysis of the respiratory centre when- 
ever an agent which first excites and then paralyses is applied 
to the medulla oblongata. 

s Quoted by Hiirthle. 
i"ioc. ci(.,p. 601. 



This conclusion is in complete accord with other evidence, 
such as the action of amyl nitrite when injected into the 
carotis, and the effect of pressure applied to the fourth ventricle. 
Cash and Dunstan, 11 in a recent paper, have shown that the 
injection of amyl nitrite into the brain arteries produces a 
marked rise of blood pressure which lasts even after the re- 
spiration shows signs of failure. So also Horsley and Spencer, 12 
in their paper " On the Changes produced in the Circulation 
and Respiration by Increase of Intracranial Pressure," show 
that if the vagi nerves are cut so as to abolish the action on the 
heart an increase of intracranial pressure causes a marked 
rise of blood pressure with a failure of respiration; in- 
deed the respiratory and vasomotor centres are so related to 
each other that, when the respiration has ceased owing to a 
moderate increase in the intracranial pressure, then a further 
increase of that pressure causes a still greater rise of blood 
pressure with the result of restarting the respirations. The 
paralysis of the vasomotor centre, in consequence of long- 
continued increase of intracranial pressure, only occurs long 
after natural respiration has been abolished, and artificial 
respiration has been employed for some time. In fact, so far 
from the same influence producing simultaneously similar 
effects upon the two neighbouring centres of respiration and 
vasomotor action, we see rather that the vasomotor centre is 
subordinate to the much more important respiratory centre, 
Nature's safeguard action being to keep up the blood pressure 
as long and as high as possible for the purpose of recovering 
the failing respiratory centre by supplying it with a large 
supply of blood. A larger supply of blood is brought to the 
brain region with the rise of blood pressure, because the evi- 
dence of physiology in recent years points to the conclusion 
that the vessels of the abdominal area and of the brain are 
not simultaneously constricted when the vasomotor centre is 
stimulated, but rather that the brain vessels behave like the 
vessels of the skin, and are dilated when the vessels of the 
abdominal area are constricted. 

These experiments upon the effect of injection of chloro- 
form into the brain arteries on the one hand, and into the 
jugular vein on the other, point strongly to the conclusion 
that the fall of blood pressure observed when chloroform is 
inhaled is due to a weakening of the heart's action, and not 
to a primary paralysis of the vasomotor centre; still, how- 
ever, as already mentioned, they cannot be regarded as a con- 
clusive proof that such is the action of chloroform when in- 
haled. We require, therefore, as a supplement to these ex- 
periments, some method by which chloroform can be inhaled 
in the usual manner, and the blood containing chloroform 
thus inhaled can be sent either to the heart alone or the brain 
alone at will. As already mentioned, we have devised the 
method of cross circulation between two animals in order to 
test this point. 

Gross Circulation Experiments. 

1. Method of Performing the Experiment and the Effects of 
Establishing the Cross Circulation.— In order that chloroform, 
when inhaled in the ordinary way, could be carried to the 
brain only or to the heart only, the circulation through the 
brain was separated from the general circulation, and a 
supply of blood for the brain obtained from another animal. 
The exact way in which this was accomplished varied in 
different experiments, for one reason because the relative 
sizes of the animals selected determined to some extent the 
number of vessels which it was considered necessary to con- 
nect from one animal to another to obtain an adequate cross 
circulation. 

In general, the plan adopted was to connect the cerebral 
ends of one or both carotids of the animal, whose cerebral 
and general circulatory systems were to be separated— and 
this animal we will speak of as the fed— to the cardiac ends 
of one or both carotids of the other animal, which we will call 
the feeder. When the remaining brain arteries of the fed 
animal were ligatured, the brain was supplied by blood reach- 
ing it by the internal carotids, and derived directly from the 
common carotids of the feeder. One external jugular vein of 
the fed animal was similarly cross connected to the cardiac 
end of one external jugular of the feeder, and the other 
external and the two internal jugul ars of the fed animal were 

11 Proceed. Roy. Soe., vol. xlix, p. 314. 
" Phil. Trans., 1891, B., p. 201. 



ligatured, so that the blood from the brain was very largely 
conducted back to the feeder, and was not allowed to reach 
the general circulation of the fed. In an experiment where a 
large bulldog of 17 kilogrammes supplied the brain of a small 
terrier of 5 kilogrammes, one carotid of the large dog was 
connected by a Y-piece to both carotids of the small dog, and 
the brain of the latter was wholly supplied by this one 
carotid. 

The larger animal was, when possible, always selected for 
the feeder ; but when rabbits were used, as there was no con- 
siderable difference in size of the animals, it was considered 
necessary to connect as many cross channels as possible from 
one rabbit to the other, so that an adequate supply of blood 
might be secured. In one such experiment both carotids and 
one subclavian of the feeder were connected severally to the 
two carotids and one subclavian of the fed, all the branches 
of the latter vessel, except the vertebral and the vessel itself 
on the cardiac side of the vertebral, being ligatured. In this 
case, therefore, blood was derived from the feeder by three 
channels, namely, the two carotids and one vertebral. The 
other vertebral of the fed animal was ligatured, and a return 
of blood was secured by one pair of cross connected jugular 
veins, the other external jugular vein of the fed animal being 
ligatured. In most cases the external carotids of the fed 
animal were ligatured, so that the internal carotids received 
all the blood derived by cross connection with the common 
carotids of the feeder. 

In all cases an adequate supply of blood was left to the brain of 
the feeder, for in no case were its vertebral arteries interfered 
with, and in some experiments one carotid was left as well. 
The blood pressure in the general circulatory system of both 
animals was registered from the femoral arteries. In order 
to reduce the tendency to the clotting of the blood the con- 
necting cannula were made as short as possible by dissecting 
out a considerable length of the vessels and by bringing their 
ends very close together. It was found convenient to suture 
together the reflected skin of the neck of one animal to that 
of the other, and so to form a bed on which the connected 
vessels could rest. It was, however, found necessary to 
diminish the clotting power of the blood by an injection of 
extract of leech or of peptone. The amount of these sub- 
stances used was small, so that the blood pressure should be 
depressed as little as possible. Moreover, the injection was 
made some considerable time before the cross circulation was 
established ; the immediate effect of the injection upon the 
blood pressure had then to some extent passed off. It will, 
however, be noticed, on reference to the protocols or the 
tracings, that the blood pressures, especially of the feeders, 
are small. 

In the experiment made on February 18th (Fig. 6), referred 
to above, the feeder, a dog of 17 kilos., received an injection 
of 7 grm. of peptone (0.4 per kilo), and two hours later, imme- 
diately before the cross circulation was established, the 
blood pressure in the femoral artery was 68 mm. (Fig. 6, 
Tracing a). This is decidedly low for so large an animal, so 
that in this case the depression caused by the injection of 
peptone had not been fully recovered from. In the fed ani- 
mal, in the same experiment the femoral blood pressure im- 
mediately before the cross circulation was established, which 
was two hours and a-half after the injection of 2J grm. of 
peptone, was 122 mm. (Fig. 6, Tracing a). The much higher 
blood pressure in this case is not due to recovery from the 
depression, caused by the injection being more complete in 
this animal than in the large one, but to the fact that at this 
moment many arteries in the neck of the small dog are 
occluded. The ascending cervical artery on the right side 
was ligatured, and the two carotids, which had been con- 
nected to the left carotid of the feeder, were still clamped. 
The left vertebral and the left subclavian were also tied, the 
ligature of the latter vessel, which was even placed proximal 
to the origin of the vertebral, being to prevent any possibility 
of blood passing by the ascending cervical arteries from 
reaching, by anastomoses, the upper part of the vertebral. 
Thus the right vertebral was the only vessel left for the 
supply of blood to the brain. Such an extensive closure of 
vessels accounts at once for the higher blood pressure in the 
fed animal as compared with the feeder. The right vertebral 
was tied as nearly as possible at the same moment as the 
clamps were removed from the carol ids and the jugular 



10 



veins (the right external jugular of the fed being connected 
with the left of the feeder), and the cross circulation in this 
way established, so that at no time was the brain of the fed 
deprived of a supply of blood. 

We are assured of this, because in no case in our experi- 
ments has there been at this moment any struggling or 
marked change in the respiration of either animal, except in 
one case, where the last brain artery was by mistake tied be- 
fore the clamps on the connected vessels were removed, as 
will be mentioned later in the description of the experiment 
on February 20th. When the cross circulation was estab- 
lished, the blood pressure in the fed animal rose still higher. 
In one minute and a-half it had risen to 160 mm., and this was 
the maximum it attained, while that in the feeder had fallen 
slightly to 58 mm. (fig. 6 b). The rise of pressure in the fed 
animal shows that there is a supply of blood from the feeder, 
and probably that the complete return of blood from the 
brain of the fed back to the feeder is not secured. In this 
particular experiment, where the right external jugular of the 
fed was connected to the left external jugular of the feeder, 
only the left external jugular of the fed was ligatured, so that 
there still remained the two internal jugulars, by which some 
portion of the blood would no doubt pass into the general cir- 
culation of the fed animal. The slight fall of pressure in the 
feeder probably also indicated that there was some bleeding of 
one animal into the other going on, but this fall would un- 
doubtedly have been much greater if a large proportion of 
the blood had not been returned by the cross-connected 
jugulars. 

This fall of pressure in the feeder does not always occur. 
In another experiment the left carotis of a dog of 12 kilos, was 
connected to the right carotis only of the fed animal, a dog of 
5 kilos. Both vertebrals of the fed were ligatured and the last 
brain artery, the left carotis, was clamped at the moment the 
cross circulation was established. The right jugular of the 
fed was in connection with the left jugular of the feeder, and 
the left external jugular of the fed was ligatured. In this 
case, also, peptone had been injected. The small dog had re- 
ceived 2.5 grm. peptone (0.5 per kilo) one hour and a-half, 
and the large dog 4.5 grm. peptone (0.3 per kilo) half an hour 
before the cross circulation was established. Just before this 
was done, the femoral pressure of the feeder was 65 mm., the 
low pressure being due to the peptone having been injected 
only half an hour previously. The femoral pressure of the fed 
at the same time was 132 mm. When the cross circulation 
was established, this slowly rose, and in one minute was 164 
mm., and that of the feeder did not in this case fall, but, on 
the contrary, rose slightly to 70 mm. 

In the experiments with rabbits, where the cross supply of 
blood was derived by three channels, there is a more marked 
loss of blood by the feeder. 

In the experiment on February 23rd (Fig. 9), one hour and 
a-half after the injection of leech extract, the femoral pres- 
sure of the fed animal was 70 mm. At this time the left 
vertebral was the only artery supplying the brain. The sub- 
clavian on the right side had been ligatured on the cardiac 
side of the vertebral, and all the other branches of the sub- 
clavian tied, so that the vertebral could by means of the 
distal portion of the subclavian be connected with the left 
subclavian of the feeder ; and the two carotids were at this 
moment also clamped and connected to the two carotids of 
the other animal. The pressure in the feeder at this moment 
was 84 mm. (Fig. 9, Tracing a). The two carotids and the 
left subclavian of this animal were then clamped. The return 
of blood was secured by the connection of the right jugular 
of the fed with the left of the feeder, the other external 
jugular of the fed being ligatured. 

When the cross circulation was established, and the last 
brain artery of the fed tied, the pressure in this animal rose, 
and in one minute and a-half was 94 mm., while that of the 
feeder fell to 44 mm. (Fig. 9, Tracing b~). This considerable 
fall of pressure of the feeder may be partly accounted for by 
haemorrhage into the fed, which must undoubtedly take place 
at first into the relatively empty vessels of the brain of that 
animal, but that this does not continue to any extent is pro- 
bably shown by the fact that the pressure did not continue to 
fall, but, on the contrary, rose slightly, and three minutes 
after the circulation was established was 53 mm. Again, the 
mere effect of closure of both carotids and of one subclavian is 



to drive the blood pressure abnormally high, and, if this is 
due to mechanical causes and not to increased activity of the 
vasomotor centre consequent on the diminished supply of 
blood to the brain, the pressure in the feeder would fall when 
these vessels are again opened. 

The rise of blood pressure in the fed animal reaches its 
maximum rather quickly, and then remains fairly constant, 
as is seen clearly in the experiments with dogs. This rise 
cannot be looked upon as due to an escape of blood from its 
brain into its general circulation. Such escape would need 
to be very large to produce the considerable rise observed, if, 
indeed, it could produce the effect at all. The explanation is 
rather one in accordance with the observations of Horsley and 
Spencer, who found that an increase of intracranial pressure 
led to a rise of blood pressure by increased activity of the 
vasomotor centre. 

Eight cross -circulation experiments were made, three with 
two dogs, three with two rabbits, and two where the attempt 
was made to supply the brain of a rabbit with blood from a 
dog. This last procedure was unsuccessful, as the rabbit in 
both cases died very soon after the cross circulation was 
established. 

2. The Effect on the Fed of Chloroform Administered to the 
Feeder. — In no experiment did we allow this condition of 
cross circulation to continue uninfluenced for any length of 
time, so that we cannot say how long the brain would con- 
tinue to be supplied with blood adequate to maintain respira- 
tion in the fed animal. In all cases as soon as the immediate 
effects of establishment of the cross circulation had passed 
off and the blood pressures of both animals were fairly con- 
stant chloroform was administered either to the feeder or to 
the fed. As chloroform given to the fee ier is carried to the 
brain of the fed the experiment corresponds to the injection 
of the drug into the carotis or vertebral and so shall be con- 
sidered before the administration to the fed, which, in so far 
as the drug has free access to the heart but is excluded from 
the brain, corresponds to the injection into the jugular. 

In the experiment on March 19th (Fig. 7) when the pres- 
sures in both dogs were constant, that of the feeder being 
100 mm. and that of the fed 160 mm. (Fig 7, Tracing d), the 
tube in the trachea of the feeder was connected with a chloro- 
form bottle and in a few seconds the blood pressure in this 
animal began to fall in the usual way and complete absence 
of the conjunctival reflex was produced in 1 min. 20 sees. The 
blood pressure of the fed animal, whose brain was receiving 
the same chloroform- carrying blood as that of the feeder, began 
after 20 sees, not to fall, but on the contrary to rise, and rose 
slowly and steadily as that of the feeder fell. (Fig. 7, Tracings 
e, A 9, h~). When the chloroform had been administered 
for 1 min. 30 sees, and the pressure of the feeder reduced 
from 100 mm. to 62 mm. that of the fed had risen from 
160 mm. to 195 mm., and then remained high, and when the 
chloroform was removed 33 sees, later, was still 195 mm. 
(Fig. 7, Tracing V). The pressure of the feeder was then 60 mm. 

As the feeder recovered from the chloroform its pressure of 
course rose, and in 1 min. 30 sees, was 88 mm., while that of 
the fed fell to 186 mm., which is still higher than it was 
before the chloroform was given. (Fig. 7, Tracing n). An ex- 
amination of the tracing shows that the rise of pressure of the 
fed was rather a quick one and then that it remained high. 
The vasomotor centre was stimulated by the chloroform and 
the excitation persisted and only very gradually passed off 
when the chloroform was removed. 

Again, in another experiment, with a pressure of 68 mm. 
in the feeder and 164 mm. in the fed, chloroform was ap- 
plied on a cloth to the nostrils of the feeder, and in 1 min. 
30 sees., its pressure fell to 40 mm., while that of the fed rose 



11 



slightly to 170 mm. ; and again, later in the same experiments 
with a pressure of the feeder of 78 mm., chloroform inhaled 
directly through a tube in the trachea caused, in fifty seconds, 
a fall of pressure to 46 mm., while the pressure of the fed rose 
from 210 mm. to 213 mm. The same effect is seen in the 
experiment on February 18th (Fig. 6, Tracing I, m, re), when 
chloroform was given to the feeder till its respiration stopped 
and its blood pressure was reduced from 50 mm. to 20 mm. ; 
the pressure in the fed at the same time rose from 162mm. 
to 180 mm., and remained high, and was 178 mm. when the 
respiration of the feeder stopped, four minutes after the 
chloroform was put on. 

That chloroform-carrying blood passes to the brain of the 
fed is moreover indicated by the abolition of the conjunctival 
reflex. This was clearly shown in the last experiment referred 
to. Immediately before chloroform was given to the feeder, 
the eye of the fed gave the conjunctival reflex ; but 1 min. 

35 sees, later the reflex was less pronounced, and 1 min. 

36 sees, later still had quite disappeared. 

These experiments conclusively show that chloroform taken 
up by the blood in the lungs in the ordinary way, and carried 
to the brain only, leads to a rise, and not to a fall of blood 
pressure. This rise can only be due to a direct or indirect 
action on the vasomotor centre. It cannot be due to increased 
intracranial pressure which might be caused by more blood 
coming from the feeder, because it takes place at a time when 
the blood pressure of that animal is tending to fall. Again, 
it cannot be considered as merely dependent on a diminished 
supply of blood to the brain, a relative anasmia, due to the 
fall of the blood pressure of the feeder, because the rise of 
pressure of the fed is usually established before the fall in the 
feeder takes place. Again, the latter is, except late in the 
administration of the chloroform, only small in extent, while 
from observations we have made on the effect of ligature 
of the brain arteries successively, it appears that a large 
diminution of the blood supply of the brain needs to be made 
to lead to a marked and lasting rise of pressure. 

The rise of pressure observed in these experiments must 
then be due, largely at any rate, to a specific action of the 
chloroform. 

Tracings of the respiration were not taken in these experi- 
ments, so that the effects produced on the respiration of the 
fed when chloroform was given to the feeder, can only be 
inferred from the respiratory undulations on the blood pres- 
sure tracing, and from such direct observations of the animal 
as were made at the time. 

The few of these from which any inference can be drawn 
only show that the respiration of the fed usually becomes 
slower one or two minutes after chloroform is given to 
the feeder. Thus in one experiment with two dogs, when the 
respiration of the fed was 14 per minute, the administration 
of chloroform to the feeder led in one minute to a reduction of 
rate to 11 per minute ; and later on, in the same experiment, 
led in one minute to a reduction of rate from 16 per minute to 
12 per minute. Again, in the experiment with two dogs on 
February 18th, the rate of respiration was reduced in one 
minute from 29 per minute to 20 per minute. In one experi- 
ment, however— namely, that on March 19th, a quickening of 
respiration was in the same time produced, namely, from 15 
per minute to 18 per minute. 

3, The Effect on the Fed of Chloroform Administered to the 
Fed.— On the other hand, when chloroform is inhaled by the 
fed animal, and is carried to the heart and all ether organs 
except the brain, a marked fall of blood pressure is always 
produced. In the experiment on February 18th (Fig. 6), 
where the blood pressure of the fed dog one minute after the 



cross circulation was established was 160 mm. (Fig. 6, 
Tracing b), the tube in its trachea was connected to the chloro- 
form bottle. After the lapse of half a minute the pressure 
began to fall at first slowly, and during the next minute and 
a-half was reduced to 136 mm. (Fig. 6, Tracings c, d, e), it was 
then falling rapidly, and in eleven seconds more — that is two 
minutes eleven seconds after the chloroform was put on, the 
tracheal tube was removed from the chloroform bottle, the 
blood pressure being 120 mm. It however continued to fall 
for twenty seconds more to 104 mm. (Fig. 6, Tracing/), and 
then began to rise, and in less than a minute and a-half had 
regained its original height of 162 mm. (Fig. 6, Tracings g, h, 
k). The chloroform was prevented by the ligature of the brain 
arteries from reaching the brain ; and that it did not do so is 
shown by the fact that the conjunctival reflex was not 
abolished, which it undoubtedly would have been in an intact 
animal supplying its own brain with blood had so extensive a 
fall of pressure occurred in consequence of the administration 
of chloroform. Again, in the experiment on March 19th, five 
and a-half minutes after the cross circulation was established, 
when the blood pressure of the fed animal was 186 mm. 
(Fig. 8, Tracing a), its trachea was connected to the 
chloroform bottle, and in one minute the pressure had 
fallen to 176 mm., in two minutes to 150 mm., and in 
three minutes to 138 mm. (Fig. 8, Tracings b,c,d,e,f.g.~) 
The chloroform, however, was not removed till four minutes 
later ; the pressure was then 132 mm. On the withdrawal of 
the chloroform the pressure began to recover, and in 43 
seconds was 140 mm. (Fig. 8, Tracing m), and in one minute 
more had reached 152 mm. (Fig. 8, Tracing re). In the 
rabbit the fall of pressure was usually more rapid, and 
the contractions of the heart were, as far as could be 
judged from the blood-pressure tracing, extremely weak- 
ened so as to be quite imperceptible. This is well seen 
in the experiment on February 23rd (Fig. 9), when chlo- 
roform given to the fed animal when its blood pressure 
was 105 mm. led to a rapid fall in one minute to 66 mm., 
in two minutes to 54 mm,, and in three minutes to 24 mm.; 
and twenty seconds later, when the chloroform was taken 
off, the pressure was only 20 mm. (Fig. 9, Tracings c, d, e). 
No indication of the beat of the heart could be seen on the 
tracing before this stage, and there was no recovery of the 
blood pressure after the chloroform was removed, for it con- 
tinued to fall still further, and in five minutes more was 
7 mm. Except for a pause in the respiration for about twenty 
seconds immediately after the chloroform was removed, the 
animal continued to breathe for the whole of this time, its 
brain being of course supplied with blood from the feeder. 
After the natural respiration had ceased, artificial respiration 
was put on for four minutes, but there was no recovery in the 
blood pressure, and a needle placed in the heart showed no 
sign of movement. 

Again, in the experiment on February 20th, when the 
blood pressure was 131 mm., the trachea of the fed animal 
was connected with the chloroform -bottle, and in one minute 
the pressure had fallen to 107 mm. (Fig. 10, Tracing 6), and 
when the chloroform was taken off thirty seconds later was 
84 mm.; the pressure was then falling rapidly (Fig. 10, 
Tracing c), and thirty seconds later the pressure had sunk to 
36 mm., and there were no longer indications on the tracing 
of heart beats. The respiration continued for three minutes 
and a-half after the indication of heart beat was lost. The 
heart was not permanently arrested, as, after an apparent 
cessation of beat for about two minutes, it commenced to 
beat again, and continued to beat slowly for about three 
minutes, and then gradually stopped. 



12 






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Fig. 6. — February 18th, 1891. Cross Circulation, Dogs. 
Peptone Injected. 

Feeder. — Left carotid connected to both carotids of fed ; left 
jugular to right jugular of fed. 

Fed. — Left subclavian proximal to vertebral tied ; right 
ascending cervical tied; both carotids connected to left 
carotid of feeder; right jugular to left jugular of feeder ; left 
external jugular tied ; left vagus cut. 





Mean 


Mean 






Time. 


Blood 
Pressure 


Blood 
Pressure 


Chloro- 
form. 


Remarks. 




of Feeder 


of Fed 






in mm. 


in mm. 






H. M. s. 










3 2 30 


68 


122 


— 


Traeing~a. 


3 2 30 


— 


— 


— 


Right vertebral of fed tied and 
cross circulation established. 


3 16 


58 


160 


Chloro- 
form on 
to fed 


Tracing 6. 


3 5 


56 


156 


— 


Tracing c. 


3 5 30 


54 


144 


— 


Tracing d. 


3 6 


54 


136 


— 


Tracing e. 


3 6 11 


54 


120 


Chloro- 
form off 


3 6 30 


52 


104 


— 


Tracing /. 


3 7 


52 


126 


— 


Tracing g. 


3 7 30 


50 


146 


— 


Tracing h; eye of fed gave con- 
junctival reflex. 


3 7 55 


50 


162 


Chloro- 
form to 
feeder 


Tracing k ; chloroform to feeder. 


3 8 15 


46 


167 


— 


Tracing I. 


3 8 30 


38 


174 


— 


Tracing m. 


3 9 30 


32 


180 


— 


Traciog n : conjunctival reflex of 
fed less pronounced 


3 11 6 


24 


168 


Chloro- 
form off 


Tracing o ; no conjunctival reflex 
in fed. 



Fig. 7.— March 19th, 1S91. Cross Circulation ; Dogs ; Chloroform 
to Feeder. (Leech Extract.) 

Feeder. — Left carotid connected to both carotids of fed. 
Left jugular connected to right jugular of fed. 

Fed. — Right vertebral, right and left ascending cervical 
ligatured. Both carotids connected to left carotid of feeder. 
Left jugular ligatured. Eight jugular connected to left of 
feeder. 





o ° a 


o o H 




a 






2oT 


SpS 




on 




Time. 


Moan B 

Pressui 

Feedei 

mm 




Chloroform 
to Feeder. 




Remarks. 


H. 51. S. 












3 23 


100 


110 


— 


— 


Tracing a. 


Pause of ?yi 


— 


— 


— 


— 


During which the above 
connections were made. 


4 9 


112 


128 






Tracing 6. At 4 h. 9 m. 30 s. 
connections between caro- 
tids opened. Connections 
between jugulars opened. 
At 4 b. 10 m. 50 s. left verte- 
bral of fed clamped, and so 
isolation of brain circula- 
tion and cross circulation 
fully established. 


4 11 


100 


163 


— 


— 


Tracing c. 


4 12 


100 


160 


— 


— 


Tracing d. 


4 12 27 


— 


— 


Chloroform 
on 


— 


— 


4 12 30 


98 


166 


— 


— 


Tracing e. 


4 13 


94 


173 


— 


— 


Tracing/. 


4 13 30 


82 


188 


— 


— 


Tracing g. 


4 14 C 


62 


197 


— 


— 


Tracing h. 


4 14 30 


60 


195 


Chloroform 
off 


— 


Tracing k. 


4 15 f 


66 


190 


— 


— 


TraciDg I 


4 15 3C 


79 


188 


— 


— 


Tracing m. 


4 16 


83 


186 


— 




Tracing n. 



Fig. 8.— March 19th, 1891. Cross Circulation ; Dogs ; Chloro- 
form to Fed. {Continuation of the Experiment illustrated by 
Fig. 7. J 



Mean , Mean 
I Blood Blood ' Chloro- 
Time. i Pressure' Pressure form to 
of Feeder" of Fed Fed. 
in mm. , in mm. I 



H. M. S. 






4 16 5 


88 


183 


4 16 20 


— 


— 


4 16 30 


90 


184 


4 17 


90 


180 


4 17 30 


90 


174 


4 18 


93 


156 


4 18 39 


93 


148 


4 19 


94 


144 


4 19 30 


90 


136 


4 20 


88 


131 


4 20 30 


86 


130 


4 21 


84 


130 


4 21 30 


82 


130 


4 22 


76 


130 


4 22 30 


72 


132 


4 23 


72 


132 


4 23 17 


— 


— 


4 23 30 


70 


135 


4 24 


70 


140 


4 24 30 


68 


146 


4 25 


68 


152 



Remarks. 



Chloro- , 
form on I 



Tracing a. 



Tracing 6. 
Tracing c. 
Tracing d. 
Tracing e. 
Tracing/. 
Tracing^. 
Tracing h. 
Tracing k. 






Tracing L 



Chloro- 
form off 



— , Tracing m. 

— Tracing n. 



Fig. 9. — February 23rd, 1891. Cross Circulation. Two Rabbits. 
{Leech Extract.") 

Feeder. — Carotids connected to carotids of fed respectively. 
Left subclavian to right subclavian of fed. Left jugular to 
right jugular of fed. 

Fed.- Carotids to carotids of feeder respectively. Eight 
subclavian tied proximal to vertebral, and with all branches 
except vertebral ligatured, connected to left subclavian of 
feeder. Eight jugular to left jugular of feeder. 





1 

Blood Blood 

Pressure Pressure 


Chloro- 
form 
to 
Fed. 




Time. 


of 


Of 


Remarks. 




Feeder 


Fed in 






m mm. 


mm. 




H. M. s. 










4 39 40 


84 


70 


— 


Tracing a. 


4 40 


\ - 




1 


Left vertebral and left jugular of 


4 n 




fed tied, and cross circulation 










established by the tbree arterial 










channels and one venous chan- 










nel. 


4 42 


48 


90 








4 43 


45 


98 





Tracing b. 


4 44 


53 


105 


Chloro- 
form to 
fed. 




4 44 30 


47 


86 


— 


Tracing c. 


4 45 


45 


66 


— 





4 46 


44 


54 




Chloroform with more air. No 
longer indication of heart beats 
on the pressure tracing. Trac- 
ing d. 


4 46 40 


44 


28 


— 


Chloroform quite strong. Trac- 
ing e. 


4 47 20 


— 


20 


Chloro- 
form off 




4 48 


44 


15 




Respiration continued at tfce slow 
rate of five per minute. Trac- 
ing/. 


4 49 


— 


10 


— 





4 50 


45 


8 








4 51 


— 


7 


— 





4 52 


— 


7 


— 





4 52 20 


52 


7 


— 


Last respiration of fed\ 



15 



Fig. 10.— February 20th, 1891. Cross Circulation between Two 
Rabbits. {Leech Extract Injected into Jugular Vein of Fed, at 
1 p.m.; of Feeder at 1. SO p.m.') 

In fed rabbit right carotis, right vertebral, and left sub- 
clavian were ligatured, so that animal only had left carotis 
open to supply the brain region. 

In feeder the carotids on both sides were prepared, but not 
tied. 



Time. 



n. ii. s. 

2 



t 33 30 
2 34 30 



2 35 30 
2 36 



2 36 15 
2 36 30 



■~ m 

555 

OS 



60 



63 



5* 

3 i 



a 

u . 



Chlo- 
roform 
to Jed 

Chlo- 
roform 
off 



Remarks. 



Leech extract injected into feeder. Pressure in 
both animals remained very constant, with 
heart beats showing plainly on both tracings. 
Leech extract injected into fed at 2h. 7 m. 30 s. 
This injection produced no effect on the 
tracing. 

Tracing a. 

The cross circulation was now begun to be 
established, but by mistake the connection 
between the left carotis of the fed and the 
right carotis of the feeder was begun first ; in 
consequence, immediately upon the ligature 
of the left carotis of the fed the brain of the 
latter was for the moment deprived of all 
blood, with the result of causing Kussmaul- 
Tenner convulsions and a threatening of ces- 
sation of respiration. Artificial respiration 
was at once put on. and the cross circulation 
as quickly as possible established by connect- 
ing together the right carotis of the fed with 
the left carotis of the feeder and the right 
jugular vein of the fed to the left jugular of 
the feeder. When the cross circulation was 
well established the artificial respiration was 
removed, and the fed animal was found to be 
breathing spontaneously without any sign of 
convulsions. The effects produced by this ac- 
cidental Ligature of the only remaining brain 
artery of the fed is very instructive, as it 
demonstrates in the clearest way the efficiency 
of the cross circulation; without cioss cir- 
culation ligature of the four brain arteries 
produces convulsions and quickly cessation 
of respiration ; with cross circulation ligature 
of the four brain arteries causes no convul- 
sions, no threatening of cessation of respira- 
tion. 

Artificial respiration off. 

The pressure on fed had been constant for half 
a minute before the chloroform was given, and 
heart beats were very visible on the tracing. 

Tracing 6. 

Tracing c. Heart beats difficult to see in tracing 
of fed, pressure falling very rapidly. 

Tracing d. 

Tracing e. Heart beats quite imperceptible in 
tracing of fed. 

Respirations of fed. 14 per minute. 

The respirations of the fed animal became 
shallower and shallower, and finally ceased at 
3.40, that is, four minutes after the end of the 
chloroform administration. Before the re- 
spirationshad ceased the slowened heartbeats 
of the fed animal reappeared on the tracing 
for a time and caused the mean blood pressure 
to rise to 56 mm. at 3.39. 



These cross-circulation experiments confirm absolutely the 
previous experiments in which chloroform was injected 
directly into the circulation. In both cases the blood 
containing chloroform excites the vasomotor centre and 
raises the blood pressure when it reaches the medulla 
oblongata, while it depresses the heart's action and lowers 
the blood pressure when it reaches the heart. 

It is, then, clearly proved that the primary fall of blood 
pressure seen during chloroform administration is not due to 
paralysis of the vasomotor centre. We must, then, look 



beyond the central nervous system for an explanation of 
this fall— that is, to a direct paralysing action of the drug 
upon the vascular system — a direct action, therefore, upon 
the heart and blood vessels. 



Criticism or the Proofs op the Commission that the 

Fall op Pressure is not due to Weakening 

op Heart. 

We have already, in the beginning of this paper, referred 
to the conflict of opinion upon the question whether, and in 
what way, chloroform affects the heart directly, and, seeing 
that the chief papers of late years have been collected together 
and published by Lawrie in the Report of the Hyderabad 
Commission, it is unnecessary to do more than refer to the 
evidence in that book as to the present state of the question. 
On the one hand, a large array of observers look upon it as 
proved that chloroform weakens the force of the contractions 
of the heart by its direct action upon the heart; on the other 
hand the Hyderabad Commission, as represented by Brunton, 
considers that chloroform only affects the heart in combina- 
tion with an asphyxial condition of the blood, and, as repre- 
sented by Lawrie, denies in toto any direct action of the drug 
upon the heart under any circumstances. To our minds it is 
perfectly clear that the weakening effect of chloroform on the 
heart is the chief, if not the only, cause of the fall of blood 
pressure seen upon administration of the drug, and it is difficult 
to understand how the Hyderabad Commission could have 
arrived at the conclusions they have published, for their 
experiments and their large number of curves confirm again 
and again the observations of others, and point directly to 
heart failure as the cause of the fall of blood pressure. 

The report of the second Hyderabad Commission consists 
of five parts, in Partv of which all the manometer experiments 
are described in detail, and remarks made upon a large num- 
ber of the individual experiments. This description of ex- 
periments and the remarks upon them, together with the 
tracings, form the most valuable part of the report, for they 
give the facts upon which the conclusions of the Commission 
are based. In their report the Hyderabad Commission do 
not state what is the reason of the fall of blood pressure so 
characteristic of chloroform poisoning ; they imply, however, 
that such fall is not due to any direct action on the heart, but 
to the paralysis of the vasomotor centre through the drug. 
The reasons for such a belief are given on p. 137 in the dis- 
cussion which follows Experiment 178. 

" Experiment 178 is very like Experiment 162, in which the 
heart's action was temporarily arrested every time the respi- 
ratory centre was paralysed. As in 162, there was no fur- 
ther fall of blood pressure during the arrest, and the beats on 
each side of the stop were ample and strong. The most re- 
markable instance of this is seen at Fig. 13. For more than 
two minutes there were only 17 very slight pulsations re- 
corded, and for over a minute of this tracing there was no 
pulsation at all. There was no fall of pressure during the 
arrest, and the Ludwig tracing shows how strong the beats 
on each side of it were. No better proof could be afforded 
than is to be found in these two experiments that direct 
weakening of the heart is not the cause of the fall of the 
blood pressure, which is inseparable from chloroform 
narcosis. 

"Experiments 64, 65, 162, 178, and 186 prove three im- 
portant points:— 1. A 'general fall of blood pressure, 
whether sudden or gradual, is not in itself dangerous. 2. 
The fall of blood pressure, which occurs in chloroformisation 
with regular breathing, is due solely to narcosis of the vaso- 



16 



motor system, and is, if not a safeguard, absolutely harmless. 
3. The fall of the blood pressure under chloroform is not due 
to weakening of the heart. The heart has nothing to do with 
producing it, unless the vagus is stimulated, or unless its 
nutrition fails either from imperfect oxygenation of the blood 
due to abnormal breathing, or from stoppage of the respira- 
tion from overdosing." 

Turning to Experiment 162, we find again the same argu- 
ment as in 178, and then follow the words : 

" If direct weakening of the heart were the cause of the fall 
of blood pressure in chloroform administration, we ought to 
find the heart beats getting smaller and smaller up to the 
time when the pressure reaches its lowest, and gradually 
growing bigger and bigger again on the other side as the 
effect of the chloroform wears off." 

According then to this argument the presumption is that 
if the beats of the heart do get smaller and smaller up to the 
time when the pressure reaches its lowest, and do gradually 
get bigger and bigger as the effect of the chloroform wears off, 
then at all events we must not exclude the weakening of the 
heart as a factor. 

In the first of the conclusions of the Hyderabad Commis- 
sion, cf. Report, p. 17, 13 the events typical of chloroform 
inhalation are described and illustrated by tracings from Ex- 
periments 168, 169, and 170; in every one of these curves 
we see that the excursions due to the heart beat as measured 
on the Fick manometer, do in the most typical manner get 
smaller and smaller as the pressure falls. 

Such curves abound throughout the tracings of the Com- 
mission, and are, as they truly say, typical of the fall of 
pressure under chloroform. Everyone who has worked at 
the action of chloroform always obtains such curves, and 
everyone would agree with the Commission that they are of 
the typical kind which would be produced, if direct weaken- 
ing of the heart were the cause of the fall of blood pressure in 
chloroform administration. 

It is somewhat surprising that the Commission should have 
laid such stress upon Experiments 64, 65, 162, 178, and 186, as to 
assert that these tracings proved that the fall of blood pressure 
under chloroform is not due to weakening of the heart, when 
they make statements just before, which, applied to their typical 
curves, show that these are of the kind that would necessarily 
occur if the chloroform did cause a fall of blood pressure 
through weakening of the heart. It is natural to suppose 
that the evidence in these cases must be very strong before 
the Commission would allow it to have sufficient weight 
to overpower the evidence of what they style their typical 
cases. As a matter of fact these cases afford no proof whatever 
that the heart's action is unimpaired by the action of chloro- 
form. In all the cases quoted the tracings afford simple 
illustrations of a peculiarity of blood-pressure tracings, 
which is well known. 

Proof from Size of Pcxse Excursions on the Pressure 
Tracings. 
The size of the excursions on the blood-pressure curve, 
however taken, due to the beats of the heart, depend upon 
the amount of blood thrown into the aorta at each beat and 
upon the extent of fulness of the aorta at the time when the 
contraction of the heart takes place. Further, the amount of 
blood thrown into the aorta depends upon the force of the 
contraction of the left ventricle and upon the amount of 
blood coming to that ventricle, which again depends upon 
the condition of the pulmonary and systemic blood vessels, and 
the extent of fulness of the aorta at the time depends upon 
the rate of heart beat, as well as its strength, and upon the 
amount of resistance to the flow of blood through the peripheral 
organs. We have then the following factors to consider : 

1. Strength of contraction. 

2. Rate of contractions. 

3. Condition of peripheral resistance. 

Both in the natural circulation and in the artificial scheme 
it is found that if 2 and 3 are kept constant and, 1, the 
strength of the contractions diminish, then the mean blood 
pressure falls and the excursions on it due to the heart beat 
are diminished in size. In fact curves are obtained precisely 
simuar to those which the Commission recognises as typical. 

u See also Lancet, June 21st, 1890, where several of the tracings referred 
to are reproduced. 



If 1 and 3 are constant, and, 2, the rate'of beat is diminished 
then it is evident that the pulse excursions on the blood- 
pressure curve are increased in size, even to a very great ex- 
tent, with a lowered blood pressure, for clearly the throwing 
in of the same amount of blood into the aorta, the walls of 
which are less tense owing to the greater length of time be- 
tween each beat, must produce a greater excursion than when 
the walls are more tense. This effect of slowing of rate ia 
very clearly seen when the vagus is stimulated. The large 
pulse excursions seen on the blood-pressure curve so charac- 
teristic of vagus stimulation do not in the least indicate any 
increise in the strength of the heart contracting, for, indeed, 
it is very probable that the contractions during stimulation 
of the vagus are slightly weaker than before the stimulation. 

If 1 and 2 are constant and 3 diminished, then the size of 
the excursions on the blood-pressure curve tend to increase 
slightly and show no sign of diminution, until the diminution 
of the peripheral resistance has reached such an extent as to 
diminish the amount of blood flowing into the heart. 

If 3 is constant and the strength of the contractions ia 
diminished, then with the diminishedhlood pressure the pulse 
excursions will be increased in size if the rate is slower, 
because more blood is able to accumulate in the heart between 
the contractions. 

If 1 is constant and 3 is diminished to such an extent as to 
diminish the amount of blood flowing into the heart, then 
with a slower rate the pulse excursions will be increased, 
because there is a longer time for the blood to accumulate 
between the contractions, and therefore more blood is thrown 
out with each beat. 

We see then that in trying to interpret the meaning of any 
alteration in the size of the pulse excursions of any curve we 
must always take into account any variation of rate, and 
especially must we bear in mind the likelihood of any increase 
in the height of the pulse excursions being due to a Blower 
rate of beat. 

If now we turn to Experiments 64, 65, etc., it is at once clear 
that their importance is greatly over-estimated by the Com- 
mission, and that the so-called proof that chloroform does not 
affect the heart, which is afforded by them, is in every case 
an instance of a slight increase of the size of the pulse excur- 
sions due to a slowing of the heart's rate. 

The first instance given is Experiment 64, and the argument 
is given as follows in paragraph 1 of the observations on the 
experiment, page 55 : — 

"9h. 14m. 20s.— Electrical irritation of peripheral ends of 
both vagi, causing an immediate fall of the blood pressure 
almost to zero. Chloroform administration was pushed 
during complete inhibition of the heart's action at 
9h. 14m. 30s. There was entire absence of pulse tracing for 
more than one and a-half minute, the blood pressure 
remained nearly at zero, and the breathing became slow. The 
irritation and the administration of chloroform were both 
stopped at 9h. 16m. 0s. The blood pressure rose immediately 
to nearly its former height. It then gradually fell, exactly as 
it does in chloroform administration with normal breathing, 
and rose again spontaneously at the end of one minute. The 
fall of pressure after the cessation of vagus stimulation con- 
stitutes the most interesting phenomenon in this observation. 
From 9h. 14m. 20s. to 9h. 16m. 0s. cardiac inhibition, with 
sudden and prolonged fall of blood pressure, was caused by 
stimulation of the vagi. The arrest of the circulation, due to 
stoppage of the heart, prevented the chloroform, which from 
9h. 14m. 30s. was saturating the air deep down in the lungs, 
from getting into the blood. But when the circulation was 
resumed at 9h. 16m 0s. the chloroform was forthwith taken 
up by the blood, and the respiration was no longer a factor in 
the process, except to eliminate it from the lungs. The effect 
of the uncontrollable absorption of chloroform into the blood 
was, not to give rise to any paralysis or weakening of the 
heart, but simply to produce the ordinary regular and gradual 
fall of the blood pressure, which is associated with narcosis of 
the nerve centres in the medulla, in normal chloroform 
inhalation." 

It is impossible to test the assertion in the last paragraph 
of this quotation, because, unfortunately, no Fick tracing 
during the slight after-fall of pressure is given. Fick 16 is a 
sample taken before the stimulation of the vagi. Fick 17 
shows the stoppage of the heart during the stimulation of the 



17 



Vagi, and Pick 18 is taken six minutes after the end of the 
stimulation of the vagi. During the after-fall of pressure in 
question a pause in the Ludwig tracing occurs, as though a 
Fick tracing had been taken, but it is not numbered, and there 
is no sign of it among the Fick curves. On the other hand 
the series Fick 12, 13, 14, 15, and 16, afford a good instance of 
the typical recovery in the size of the pulse excursions after 
an excessive fall of pressure due to chloroform. 

Experiment 65 is a fairly good instance of the effect of 
change of rate upon the magnitude of the pulse excursions. 
Thus Fick 4 in the series Fick 3, 4, 5, 6, gives larger excur- 
sions than Fick 6, owing to the much slower rate, although 
the mean pressure is higher in the latter curve. So also in 
Fick 8, 9, 10, the slowing of the heart produced by stimula- 
tion of the central end of the right vagus produces a larger 
pulse excursion. 

Finally, the series Fick 12, 13, 14, 15, 16, 17, 18, 19 show most 
clearly the dependence of the size of the pulse excursions 
upon the rate, and also the manner in which the excursions 
of the pulse are diminished by chloroform. It is specially 
instructive to compare Fick 14, 15 with Fick 16, 17. 

Experiment 162. In the observations on this experiment, 

E. 126, the Commission say: "If direct weakening of the 
eart were the cause of the fall of blood pressure in chloro- 
form administration, we ought to find the heart beats getting 
smaller and smaller up to the time when the pressure reaches 
its lowest, and gradually growing bigger and bigger again on 
the other side as the effect of the chloroform wears off. In- 
stead of this, Experiment 162 shows that there were ample 
pulsations on both sides of the temporary pauses. If Fick 9, 
with the Ludwig tracings on either side, is carefully studied, 
it will be seen that up to the time the heart beats ceased, the 
pulsations recorded in the Ludwig were ample and strong. 
There was then a temporary arrest of pulsation for 6 seconds 
{vide Fick 9). Immediately after Fick 9 the pulsation re- 
turned for 5 seconds (vide the Ludwig between 3h. 28m. 0s. 
and 3h. 29m. 0s.). Afterwards there was a long pause of 20 
seconds without any pulsations at all. This pause was so 
marked that Dr. Bomford thought a clot had formed in the 
tube, and at 3h. 29m. 10s. he wrote on the Ludwig tracing 
' ? clot.' Artificial respiration was just about to be com- 
menced when the animal gave two spontaneous gasps ; 
vigorous pulsations followed, and the pressure was raised in 
5 seconds to the height it was at before chloroform was ad- 
ministered in Observation C." 

Now the Commission, at the instance of Dr. Lauder Brunton, 
arranged purposely so that a mercury manometer tracing 
should be taken on a very slowly-running drum, for the pur- 
pose of seeing at a glance a record of a long blood pressure ; 
in order at the same time to obtain a record of the pulsations, 
they arranged so as to connect up at will with a Fick man- 
ometer, which should register on a quickly-moving drum ; 
and naturally all their conclusions as to size of heart con- 
tractions are drawn from the Fick tracings, while their con- 
clusions as to fall of blood pressure are drawn from the Lud- 
wig tracings. Whenever it was thought advisable during the 
Ludwig tracing to obtain a record of the pulse excursions, the 
Ludwig tracing was interrupted for a short time, and a trac- 
ing made with the Fick. This was done also in Experi- 
ment 162, with the result that the Fick tracings show in 
this instance, as in others, a diminution of the pulse excur- 
sions during the chloroform administration even to invisi- 
bility. These Fick tracings, 6, 9, 12, are taken in the ordinary 
way as samples, when the blood pressure has fallen very low, 
at a time when, according to the report, the Ludwig tracing 
showed that the heart was beating well and regularly, with- 
out any indication of any stoppage, and yet the sample taken 
with the Fick shows stoppage of the heart according to the 
Commission, in all three instances. We must say that any 
physiologist ought to have been very chary of drawing con- 
clusions from an experiment in which the mere shifting of 
the tracing from the Ludwig to the Fick kymograph, and 
vice versii, causes the contractions of the heart to disappear and 
reappear again respectively. As far as the heart pulsations are 
concerned, the Fick manometer is the guide to which the 
Commission has trusted throughout (except in this instance 
and in Experiment 178) and in Fick 6, it is clear that the pul- 
sations are still visible, and even in Fick 9 the line is not per- 
fectly even ; very faint indications of pulsations are visible on 



it. As to the movements recorded in the Ludwig tracing on 
each side of Fick 9, upon which the Commission lays so much 
stress, even if they were due to contractions of the heart, 
they would not overweigh the positive evidence of the Fick 
tracing. There is no need, however, to suppose that they 
are evidence of heart contractions only ; it is quite possible 
that they are due partly to heart beats and partly to respira- 
tory movements so feeble as not to have been noticed by the 
observers who recorded cessation of respiration 55 sees, before 
Fick 9 was taken. If this were so, the true cessation of respi- 
ration would be signalled by the pause of 20 sees., which Dr. 
Bomford thought showed a possible clot in the cannula. 
Further, when artificial respiration was just about to be 
commenced the animal gave two spontaneous gasps, etc., 
showing that the respiratory centre was able to recover 
of itself, and was therefore not so very deeply affected by the 
chloroform. It is, however, impossible to argue about the 
excursions on a blood-pressure tracing, taken with a mercury 
manometer on a very slow-moving drum, without the simul- 
taneous graphic record of the respiratory movements. 

It is sufficient to point out that Experiment 162 gives no 
scientific evidence whatever that direct weakening of the 
heart is not the cause of the fall of blood pressure in chloro- 
form administration, but, on the contrary, it confirms the 
other tracings of the Commission, that such weakening of the 
heart is, in all probability, the cause of the blood pressure 
fall. 

The observations of the Commission on Experiment 178 
have been already quoted. Here again we see, as in Ex- 
periment 162, that the Commission disregards the evidence 
of the Fick tracings, and places reliance upon the Ludwig 
tracings as to the strength of the heart beats, and yet the Fick 
tracings in this experiment throughout give the most typical 
curves of the steady diminution in the pulse excursions as 
the pressure falls ; this is especially well seen in the series, 
Fick 14, 15, 16, 17, 18, 19, and also 20, 21, 22, 23, 24, 25, 26, 27. 
The series 4, 5, 6, 7, 8, 9 illustrate the effect of a slower rate 
on the size of the excursions ; so also do the series 10, 11, 12, 
13, in which the combined effect of the weakening of the 
strength and the slowing of the rate of the contractions is well 
shown. In Experiment 186 no Fick tracings are given, and 
the Ludwig tracing on the slow drum gives no possibility of 
coming to any conclusion as to the condition of the heart. 

It is perfectly clear, then, that this part of the so-called 
proof given by the Hyderabad Commission of the absence of 
any direct effect upon the heart when chloroform causes a 
fall of pressure is no proof at all; but, on the other hand, all 
their curves yield evidence to the exact contrary. 

Peoop from Injection into Jugulab. 

So also the second part of their proof, as given in paragraph 19 
of their conclusions, namely : " " On the other hand, it seems 
clear from Experiment 92 that the direct action of chloroform 
on the heart's substance is not the cause of the fall of pressure 
that occurs when it is inhaled," is equally inadequate. Ex- 
periment 92 is one of a series of experiments in which chloro- 
form was injected into the jugular vein and so directly to the 
heart. In this experiment the jugular vein was tied, and then 
injections of chloroform were made into it as follows : 20 m 
at 8 h. mins. ; 20 m at 8 h. 2 mins. 30 sees.; 20 m at 
8 h. 3 mins. 45 sees. ; 20 m at 8 h. 5 mins. 45 sees. At 
8 h. 5 mins. it was noticed that the cornea was not sensitive, 
but no observation was made before that time as to whether 
the cornea had been sensitive. Before the last injection no 
appreciable effect was produced on the blood pressure or on 
the respiration. Then after the last injection a rapid marked 
fall of blood pressure occurred. In other words, owing to the 
jugular being tied the injection did not really travel to the 
heart, but accumulated in the tied vein. In our experiments 
the chloroform was always injected into the vein directly by 
means of a hypodermic syringe, so that the circulation in the 
vein was bound to carry it on ; in no case was it found pos- 
sible by us to inject four doses of even 2 m each before 
producing a fall of blood pressure. 

Then at 8 h. 13 mins. 20 n and at 8 h. 14 mins. 20 m were 
injected, followed by a still further fall of blood pressure, 
and then at 8 h. 33 mins. it was noticed that the cornea was 
slightly sensitive, the blood pressure at this time being on the 

u Report, p. 21. 



18 



rise. In other words, after the injection of 120 m of chloroform 
into the vascular system in addition to what had been given 
previously to a dog weighing 33J lbs., the cornea was sensi- 
tive half an hour after the first injection. Then at 
S h. 40 ruins. 30 sees, another 20 m injected ; at 
8 h. 42 mins. 30 sees, cornea still sensitive. At 8 h. 
43 mins. 15 sees, another 20 in injected ; at 8 h. 45 mins. 
cornea insensitive with a falling blood pressure. At 8 h. 
46 mins. another injection of 20 in ; and at 8 h. 53 mins. 30 sees, 
respiration stopped with blood pressure very low ; at 8 h. 
04 mins. thorax opened, heart perfectly still, not irritable; 
and at 8 h. 55 mins. 30 sees, gasping from regular rhythmical 
movements of the diaphragm. 

It appears to us that the conclusion to be drawn from this 
experiment is that a large amoust of the chloroform injected 
stayed in the jugular vein, and was only gradually brought 
into the circulation. It is difficult to conceive that after so 
large an amount the cornea could have been still sensitive if 
it had been all in circulation. 

The experiment seems to point directly to a weakening 
of the heart's action, especially when we find that only thirty 
seconds after the cessation of respiration the heart is de- 
scribed as perfectly still, not irritable. 

From a similar examination of Experiment 91 we conclude 
that as in Experiment 92 no appreciable amount of chloro- 
form reached the circulation until the fourth injection, and 
then the fall of blood pressure was not incompatible with the 
action of chloroform on the heart. 

We conclude then that the experiments of the Hyderabad 
Commission, as well as our own, give no support to their con- 
clusion that the fall of blood pressure in chloroform adminis- 
tration is not due to any weakening of the heart's action, but 
on the contrary their curves if rightly interpreted agree abso- 
lutely with our own, and both confirm the commonly accepted 
view that the fall of blood pressure due to the action of 
chloroform is mainly caused by the weakening of the heart's 
contractions. 

Action of Chloroform on Blood Vessels Dlrectlt. 

Finally the fall of blood pressure may be due not entirely 
to the action of the drug upon the heart, but also to its direct 
action upon the blood vessels. It is clear that a fall of pres- 
sure might be caused by the action of a drug upon the blood 
vessels, both if the drug causes constriction and also it it 
causes dilatation of blood vessels. In the first case the vessels 
to be constricted must evidently be the pulmonary vascular 
system, and any long continued fall must mean so excessive 
a constriction of the pulmonary vessels as greatly to hinder 
the passage of blood from the right to the left side of the 
heart. The physiological result of such a hindrance must 
manifest itself in two ways : (1) the right side of the heart 
must become greatly distended with blood while the left side 
remains empty, and (2) the pressure in the pulmonary artery 
must rise as the pressure in the systemic aorta falls. Such a 
condition of the pulmonary vessels has been asserted lately 
by Johnson 15 to be typical of the asphyxial condition, and he 
says that in all cases of death by asphyxia this condition is 
manifested by the enormous size of the right side of the 
heart and the remarkable whiteness of the lungs, due to the 
peisistent contraction of the pulmonary vessels even after 
death. 

Seeing the possibility that asphyxial conditions may play 
a decided part in death from anaesthetics such as ether and 
chlorof jrm, we have made a few experiments for the purpose 
of testing the meaning of this extreme whiteness of the lungs 
when the animal is killed by occlusion of the trachea, and 
have found that the phenomenon depends upon the phase of 
respiration at the time when the tracheal tube is closed; if 
the lungs are distended in inspiration and the trachea closed 
at this moment, then upon death the symptoms described by 
Johnson are most manifest ; if, on the other hand, the trachea is 
closed at the height of expiration, then upon death the lungs 
present the usual reddish colour and no sign of vascular 
constriction is to be seen. The phenomenon depends clearly 
enough on the emptying of the lung vessels by pressure and 
not by vascular constriction. There is, then, as far as we 
knew, no evidence that the asphyxial condition brings about 
any special contraction of the pulmonary vessels, and so, too, 

15 Proc. Roy. Soc, x'ix, 144. 



there is no evidence that chloroform causes a contraction of 
those vessels, but rather evidence against it. The important 
point is the observation of Bradford that the pressure in the 
pulmonary artery, as measured from a branch, does not rise 
when chloroform is given, but falls pari passu with the pres- 
sure in the systemic aorta ; such an experiment is the 
natural result if the fall of pressure in both is due to a 
weakening of the central organ— the heart, but is impossible 
if the fall of pressure in the aorta is due to the chloroform 
causing an obstruction to the flow of blood through the 
lungs. 

Further, the observations of McWilliam point to a dilatation 
of both sides of the heart as the effect of chloroform and not 
of the right side only ; and although in the absence of any 
tracings, and with a feeling of doubt as to the validity of the 
methods employed by McWilliam, we are not prepared to 
agree to all his statements, yet we can say with confidence 
that in a number of cases where the heart appeared dilated 
after death from chloroform, both sides were dilated. 16 

There is no evidence, then, that the fall of blood pressure is 
due in any way to obstruction of the flow of blood through 
the lungs. There remains the question whether it is due to 
any extent to a direct relaxing influence of chloroform upon 
the muscular tissue of the systemic vascular system. Such an 
action is a priori probable because of the close relationship 
between the muscular tissue of the heart and blood vessels ; 
there is, however, no evidence that direct vascular dilatation, 
owing to the presence of chloroform in the blood, plays any 
great part in the fall of blood pressure. 

The original experiments of Lister showed that not only a 
drop of chloroform when applied, but also the vapour of 
chloroform, was able to produce hyperemia in the web of the 
frog's foot. The evidence, however, of any direct dilatation 
of vessels when chloroform is inhaled does not appear to 
exist, and, in fact, in such a book as Dastre's, on antesthetics, 
the pallor of the face so often noticed is considered to indi- 
cate vascular constriction as the effect of the drug rather than 
vascular dilatation ; but, as far as we can gather from his book, 
we see no reason to suppose that the pallor cannot be explained 
by weakening of the heart. Roy and Sherrington" assert that 
chloroformcauses constriction rather than dilatation of the ves- 
sels of the brain, while, on the other hand, Hiirthle 13 from his 
experiments finds at first dilatation of the brain vessels as the 
direct effect of chloroform. This is followed shortly before 
death by constriction. We ourselves have tried to produce a 
fall of blood pressure by allowing chloroform vapour to pass 
in and out of the abdominal cavity through two openings as 
far removed from one another as possible, expecting that a 
local dilatation of the vascular area governed by the splanchnic 
nerves might be produced in this way, and so lead to a con- 
siderable fall of blood pressure. The experiment was, how- 
ever, negative, and gave no indication that the blood pressure 
fall of ordinary chloroform inhalation was to any degree 
whatever due to direct dilatation of the abdominal vascular 
area. The volume of such an organ as the spleen does cot in- 
crease when chloroform is given to the animal, as it would if 
a dilatation of its vessels or a relaxation of its muscular tissue 
occurred, but, on the contrary, diminishes more than can be 
accounted for by the fall in general pressure, showing that 
there is some active constriction. From these imperfect 
observations we are inclined to think that whatever action 
chloroform has directly on the blood vessels, it is insignifi- 
cant compared with its much greater effects, primary and 
secondary, indirectly through the vaso-motor centre. 

The Dangers of Chloroform Administration. 
The conclusions and report of the Hyderabad Commis- 
sion deal with two distinct and separate questions (1) the 
physiological action of chloroform, and (2) the dangers 
of chloroform administration. We have already discussed 
the first question, and have shown why in our opinion 
the physiology of the Commission is wrong; it is there- 
fore with all the greater pleasure that we can now turn 
to the second question, and state that in our opinion the 
principles which have guided Lieutenant- Colonel Lawrie 

16 The tracings have now'been published in Journ. o Physiol., xii, Deo 

1S92. 

17 Jown. ot Physiol., vol. xi, p. 97. 

18 Ptiioer's Archie, vol. xliv, p. 596. 



19 



in the administration of chloroform are entirely in the 
right; that the great value of the Hyderabad Commission, 
for which the thanks of the medical profession will always be 
given to H.H. the Nizam, is the confirmation of Lawrie's 
views as to the safe method of administering chloroform, and 
also the publicity which has been given to the fact that by 
this method chloroform has been administered to many 
thousands of persons, not by experienced anaesthetists but by 
the students of the hospital without the occurrence of a 
single death. 

The principle upon which Lawrie administers chloroform 
may be summed up in a single sentence : " Never at any mo- 
ment of the administration of chloroform administer it in so 
concentrated a form as to cause irregularity of respiration, 
and cease the administration as soon as complete anaesthesia 
has been induced." Nature herself provides the signs and 
symptoms which show when the drug is being given in too 
concentrated a form, for when the air breathed contains too 
great a percentage of chloroform vapour the animal en- 
deavours in three different ways to safeguard itself against 
the poisonous vapour ; it struggles for the purpose of getting 
away, it holds its breath for the purpose of not taking more 
in, and its heart stops beating for the purpose of not sending 
on the poison to the nerve centres. Great credit is due to the 
Hyderabad Commission for their strong insistence upon the 
safeguard action of these three occurrences. Snow had pre- 
viously pointed out the absence of danger from holding the 
breath and from stoppage of the heart, as already mentioned, 
but the experimental evidence of the safeguard action of the 
vagus nerve is due to the Hyderabad Commission. The result 
of the struggling is to increase the rate and depth of the 
respirations and to raise the blood pressure, owing, accord- 
ing to Zuntz and Geppert, 19 to the action of the products of 
muscular activity in the blood. 

The result of holding the breath is an after-increase of 
respiration and the stoppage of the heart through the vagus 
is followed by a reaction in the opposite direction, so that as 
Snow points out and as the Commission emphasises, there is 
now a danger of an excessive amount of chloroform being 
taken in, with the evil results of over-concentration. 

The logical conclusion is, as Lawrie points out, to remove 
the chloroform further from the face until the blood pressure 
and respiration have recovered, and seeing that the respira- 
tion is so easily and markedly affected, he fixes his attention 
on that and says— Wait till the breathing is regular before the 
chloroform is again placed nearer the face. 

What is the danger of concentration ? 

Snow says the heart is only affected when the chloroform is 
given in too concentrated a form. 

Lawrie says pushing chloroform overpowers the respiration 
and then the heart fails. 

Cushny 20 says that too great concentration affects the heart. 

Brunton considers the sequence of events to be as follows : 
first, the respiration is affected, with the result of causing an 
asphyxial condition of the blood, and then the combined 
action of chloroform and asphyxia affects the heart. 

We see here another instance of an ever-recurring difficulty 
in physiological investigations, namely, to determine which 
is cause and which is effect ; with an overdose, does death 
take place through weakening of the heart or through failure 
of the respiration ? 

What is true is this, as pointed out by the Hyderabad Com- 
mission — the respiration stops before the heart actually ceases 
to beat. This, however, does not necessarily imply that an 
overdose kills by its action on the respiration. Such a death 
may bebroughtabout in two ways : 1. Weakeningof respiration, 
causing insufficient aeration of the blood, which in its turn 
causes heart failure, through the combined action of asphyxia 
and chloroform. 2. Weakening of heart, causing an insuffi- 
cient blood supply to the respiratory centre, which in its turn 
causes cessation of respiration through the combined action 
of chloroform and an insufficient blood supply. 

In both cases the chloroform affects both heart and respira- 
tory centre, in both the respiration stops before the heart 
ceases to beat ; but (1) is a case of death from respiration 
failure mainly, and (2) from heart failure mainly. The rapid 
fall of blood pressure due to an overdose is clear evidence of a 

« Pfliiger's Arch., xxxviii, 337 
20 Lancet, March 14th, 1891. 



weakening of the heart, as already proved ; so that if our 
statements are accepted, it follows that the first explanation 
is less likely than the second. In our experiments we have 
seen very distinct evidence that the respiratory centre is 
much more easily affected by chloroform when its blood sup- 
ply is diminished to a considerable extent. 

Chloroform: with Diminished Blood Supply to the 

M EDULLA. 

We have been very much struck, both in the experiments 
on cross circulation and on the effect of ligature of the brain 
arteries, to find that, after the occlusion of two or more of the 
brain arteries, a very slight amount of chloroform inhaled is 
sufficient to stop respiration ; the respiratory centre is appa- 
rently working at a great disadvantage with an insufficient 
supply of oxygenated blood, and is therefore easily placed 
hors de combat by any paralysing agent, such as chloroform. 

In our cross-circulation experiments we attempted in a few 
cases to keep alive the brain of a rabbit by the blood from a 
dog, but found that the experiment was unsuccessful, as the 
rabbit always succumbed soon after the cross circulation was 
established. In these cases, then, we continued an experiment 
upon the dog, and noticed the effect of chloroform when two 
or three of the brain arteries were ligatured. Thus March 2nd 
and February 27th, 1891, were two instances, and in them we 
see another most striking result of chloroform under these 
circumstances, namely, the production of periodic respirations 
of the nature of Cheyne-Stokes respiration. 

The amount of chloroform taken into the trachea of the dog 
was regulated by a slit in the cannula which could be left 
open or closed to a greater or less extent. When it was wide 
open only a small amount of chloroform was mixed with the 
air of inspiration, in fact under these circumstances a normal 
animal will continue breathing in a small amount of chloro- 
form for a long time without any sign of danger. When the 
slit is completely closed the whole air of inspiration passes 
over the chloroform in the Wolff's bottle, with the result of 
causing a rapid fall of blood pressure and a speedy threatening 
of cessation of respiration. 

In these cases, however, where two or more of the brain 
arteries were ligatured the connection of the tracheal cannula 
with the chloroform bottle, even when the slit was wide open, 
was sometimes sufficient to cause a marked alteration of the 
respirations of the nature of Cheyne-Stokes respiration. 
Thus on March 2nd, after both carotids were clamped, the 
chloroform bottle was connected with the trachea, the side slit 
being fully open, and the respirations, which were slow at the 
time, became quickly weaker and ceased in about one minute, 
the animal then remained for over one minute without breath- 
ing, then the respirations began again, quickly getting 
stronger and again dying away, till another pause of over a 
minute took place; the period of respiratory activity lasted 
about a minute, and during the whole time the trachea was 
in connection with the chloroform bottle, the slide slit being 
fully open. During the periods of respiratory activity the 
blood pressure rose ; during the pauses it fell slightly. After 
the last pause the respirations again recommenced and then 
one carotis was undamped, with the result that the respira- 
tions continued regularly with a regular blood pressure until 
by closing the side slit the chloroform was pressed and a rapid 
fall of blood pressure with cessation of respiration took 
place. 

We conclude, then, that the respiratory centre is better able 
to resist the paralysing action of chloroform when it is 
freely supplied with oxygenated blood than when it is be- 
coming exhausted by an insufficient supply of blood insuffi- 
ciently aerated, and that Lawrie's supposition that the fall of 
blood pressure is in itself of the nature of a safeguard, be- 
cause of the diminished amount of chloroform conveyed to 
the medulla oblongata, is not at all likely, as the smaller 
amount of chloroform so conveyed is more effective on the 
centre already suffering from want of a sufficient blood sup- 
ply. The only safeguard action throughout is at the com- 
mencement of the chloroform administration, as already 
mentioned, when we see struggling, stoppage of heart, and 
holding of breath. Afterwards, when anaesthesia is induced, 
the fall of blood, pressure, which is due to weakening of the 
heart, is no safeguard, but, on the contrary, is a danger to be 
avoided as far as possible. 



20 



Chlobofobm with Plenty of Am. 

The rapidity and depth of this fall is directly dependent 
upon the concentration of the chloroform, so that if care 
is taken to give the chloroform with plenty of air it is 
possible to obtain anaesthesia with very little fall of pres- 
sure, for the heart is very little affected by blood containing 
only a small amount of chloroform. On the other hand, 
administration of chloroform with plenty of air, continued 
after complete anaesthesia has been produced, does ultimately 
overpower the respiration, although the heart is beating 
sufficiently well to maintain the blood pressure at a fairly 
good level. 

These statements are well illustrated by an experiment on 
December 11th, 1890 (Fig. II), 21 where chloroform was ad- 
ministered to a rabbit continuously for a long period of time 
by dropping it on to a cloth placed round the head of the 
animal in a conical shape, so as to leave a free opening for air 
about two inches in diameter. Every now and then the part 
of the cloth upon which the chloroform was poured was 
brought closer to the nose and mouth of the animal, and the 
moment of bringing the chloroform nearer and of removing it 
again was noted on the kymograph paper. In the tracings a, 
b, c, d, e, /, Fig. 11, samples of the respiration and blood- 
pressure curves are given at various times throughout the ex- 
periment ; as stated already, chloroform was steadily ad- 
ministered during the whole time. 

In Tracing a, taken before the administration of chloroform 
at 3.34 we see : mean blood pressure, 64 ; pulse rate per 
minute, 222 ; respiration rate per minute, 30. The chloroform 
was then placed on the cloth, and the effect of bringing the 
chloroform nearer and removing it further tried for a number 
of times. An example of the effect produced is given in 
Tracing b, showing the inhibition of the respiratory move- 
ments, the slowing of the pulse, and the rise of blood pressure 
owing to the stimulation of the trigeminal and pharyngo- 
Uryngeal nerves, when the chloroform is more concentrated ; 
immediately the cloth is removed further from the nose the 
blood pressure returns to its normal condition, and the 
slowened respiration gradually quickens up to its previous 
rate. This experiment was repeated again and again with 
similar results. 

The effect of the continuous administration of chloroform in 
this way for 14 minutes is given in Tracing c, taken at 4.48, 
where we see : mean blood pressure, 67 ; pulse rate per 
minute, 218 ; respiration rate per minute, 31. Further con- 
tinuation of the same experiment shows that the inhibition 
oE the respirations and the slowing of the pulse when the 
chloroform is brought nearer to the nose become less 
marked ; and, finally, after 3.56— that is, 22 minutes after the 

21 Bbitish Medical Joubnal, January 28th, 1893, p. 169. 



beginning of the experiment— the blood pressure and the 
respirations remained absolutely unaffected when the chloro- 
form was brought close to the nose. At the same time, it was 
noticed that the corneal reflex was entirely abolished. 

Tracing d, at 3.57, shows the absence of any effect upon 
temporary concentration of the chloroform, and we see : mean 
blood pressure, 69 mm. ; pulse rate per minute, 204 ; respira- 
tion rate per minute, 42. It is noticeable that at this period, 
when all reflexes were abolished and the animal was in a con- 
dition of complete anaesthesia, the blood pressure was not 
lower than before the commencement of the experiment, and 
the only sign of the action of the anaesthetic is to be found in 
the quicker respiration. 

At 3.58 the respiration rate per minute had increased to 46, 
the pulse tracing and respiration both remaining absolutely 
regular. At 3.59 the respiration was 45 per minute, at which 
it remained till 4.1, the mean blood pressure being then 
62 mm. Both respiration rate and blood pressure continued 
steadily to diminish, and at 4.3, when Tracing e was taken, we 
see: mean blood pressure, 50 mm.; pulse rate per minute, 
218 ; respiration rate per minute, 37. At 4.5 the respiration 
rate was 35; at 4.7, 31 ; at 4.8,29; and at 4.9 the respiration 
had ceased. The termination of the experiment is shown in 
Tracing f, in which is seen the diminishing force of the dia- 
phragm contractions, with the final rate, and we see : mean 
blood pressure, 48 mm.; pulse rate per minute, 126; respira- 
tion rate per minute, 24. 

It is noticeable in this case, as in others (Figs. 1, 2, and 3), 2J 
how markedly the musole strip of the diaphragm elongates 
when the respiration is failing. This points strongly to the 
conclusion that the respiratory centre possesses a distinct 
tonic influence on the diaphragm muscle, so that the failure 
of its action causes a loss of tone in the muscle as well 
as a diminution in the strength of each contraction. The 
pressure of 48 mm. at the time when the respiration ceased 
is not very low for a rabbit, and, indeed, the heart continued 
beating well for a considerable time, and then, by means of 
artificial respiration, the animal was easily recovered, and 
both blood pressure and respiration became normal, as is 
seen in Fig. 1, Tracings a and b, which represent the final 
ending of the experiment. 

The danger, then, of chloroform administration consists (1) 
of causing a serious fall of pressure owing to weakening of 
heart from too great a percentage of chloroform in the air, 
which, combined with the action of the chloroform on the 
respiratory centre, in its turn causes failure of respiration ; 
and (2) cessation of respiration after long administration 
owing to keeping on the chloroform, although given with 
plenty of air, too long a time after complete anaesthesia has 
been established. 

22 British Medical Joubnal, January 2ist, 1893, p. 198. 



i